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DEMS > Unit II week 2 > Flashcards

Unit II week 2 Flashcards

1
Q

Rank in order from most polar to nonpolar:

free fatty acids
cholesterol
cholesterol esters
triglycerides
phospholipids
A

Most polar: fatty acid

  • -> phospholipids
  • -> cholesterol
  • -> triglyceride
  • -> cholesterol ester (most nonpolar)
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2
Q

Types of specialized lipids: (4)

A

1) Phospholipids
2) Sphingolipids
3) Glycosphingolipid
4) Molecules made from arachidonic acid

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3
Q

Glycerophospholipids

structure

A

glycerol backbone + PO4 group attached

located at interface of lipid and aqueous in membranes or at the surface of lipoproteins

amphipathic molecule

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4
Q

Glycosphingolipid

structure

A

ceramide backbone + sugar residue on head group

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5
Q

De Novo Lipogenesis occurs when _______ is present in ______ or _______ tissues in excess

A

glucose

liver, adipose

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6
Q

De Novo Lipogenesis

1) Acetyl CoA + ________–> ______ (leave ______ and enter ______)
2) Citrate –> _______ in the ________
3) Acetyl CoA –> ________ via _______ enzyme
4) ______ CoA units are put together 2 carbons at a time by _________ (enzyme) to form growing fatty acid chain (first 2 carbons from ______ CoA)

A

1) Acetyl CoA + OAA→ citrate (leave mitochondria, enter cytosol)
2) citrate –> aceyl CoA (cytosol)
3) Acetyl CoA → Malonyl CoA by acetyl-CoA carboxylase
4) Malonyl CoA units are put together 2 carbons at a time by fatty acid synthase to form growing fatty acid chain (first 2 carbons from acetyl CoA)

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7
Q

Malonyl CoA

inhibits _________

A

important intermediate of fatty acid synthesis

Inhibits Carnitine Palmitoyl Transferase 1 (CPT-1)
–> Inhibits Beta-oxidation of fatty acids (pathway going in opposite direction)

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8
Q

Fatty acid synthase

A

Uses NADPH (hexose monophosphate pathway) for energy

Converte malonyl CoA —> fatty acids (palmitate) via addition of carbons 2 at a time

first 2 carbons come from acetyl CoA

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9
Q

Acetyl-CoA carboxylase

why is it important? what reaction does it catalyze?

Activated by _______
Inhibited by ____________

A

Converts Acetyl CoA → Malonyl CoA

Rate limiting step in fatty acid synthesis

Activated by citrate
Inhibited by long chain fatty acyl CoA

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10
Q

Fatty acids are packaged with ______ –> ________ –> circulate in blood as ________

Then taken up by adipose tissue through _________ –> stored and used when body is in negative energy balance

A

glycerol –> triglyceride
VLDL

Lipoprotein lipase

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11
Q

Hormone sensitive lipase

A

insulin low, counterregulatory hormones high → breaks down triglyceride in adipose tissue

Releases fatty acids and glycerol → enter circulation, taken up by liver

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12
Q

Beta oxidation

A

occurs when body in negative energy balance (exercise, short-term fasting)

Provides source of energy to preserve glucose for the brain and provides energy (ATP) needed for gluconeogenesis in liver

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13
Q

Steps of Beta oxidation

1) __________ breaks down ________ releasing fatty acids and glycerol into circulation –> taken up by ________

2) Once there…
Glycerol –> substrate for ________
Fatty acid –> __________

3) Fatty acid in _______ of hepatocyte –> converted to __________ –> enters _______ via ______________
4) 2 carbons at a time removed from _________ as ________ –> can enter __________ pathway

A

1) Hormone sensitive lipase, triglycerides, liver

2) glycerol = substrate for gluconeogenesis
Fatty acids = energy source for gluconeogenesis

3) cytosol, converted to acyl-carnitine
enters mitochondria via carnitine palmitoyl transferase 1 (CPT1)

4) 2C removed at a time from fatty acyl CoA as acetyl CoA –> can enter TCA cycle

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14
Q

Ketogenesis

A

insulin very low/absent, counterregulatory hormones high (long-term fasting, ketogenic diet, DKA)

Acetyl CoA produced by B-oxidation in liver can become a ketone body

Ketones = alternate fuel for brain and other tissues in states of prolonged dietary glucose insufficiency

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15
Q

Ketone bodies formed during: ________, _________, and _______

because of what 3 conditions?

A

starvation, DKA, alcoholic ketoacidosis

1) Very low insulin levels
2) High counterregulatory hormones
3) Abundant source of substrate (fatty acids, ethanol)

**Ketones only formed when acetyl CoA produced by fatty acid metabolism (or ethanol metabolism) exceeds capacity of TCA cycle to metabolize it (ATP/ADP is high)

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16
Q

HMG CoA synthase

A

rate limiting step in ketogenesis (synthesizes hydroxyl methylglutaryl CoA)

Occurs in mitochondria

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17
Q

Cholesterol synthesis

Cholesterol synthesis from _______ through formation of ________

rate limiting step?
location in cell?
does it require energy?

A

Cholesterol synthesis from acetyl CoA through formation of hydroxymethyl glutaryl CoA

  • *HMG CoA Reductase: rate limiting step in cholesterol synthesis
  • Occurs in cytosol
  • Uses NADPH for energy
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18
Q

Lipoprotein pathways: 3 pathways

A

1) Dietary fat pathway (Chylomicron pathway)
2) VLDL pathway
3) HDL pathway

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19
Q

Fatty Acids

A

hydrophobic hydrocarbon chain + terminal carboxyl group (- charge in body)
Amphipathic nature

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20
Q

Long chain fatty acids

A

hydrophobic portion predominates, water insoluble, transported in circulation with proteins

Typically components of cell membranes

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21
Q

Saturated vs. unsaturated fatty acids

A

Saturated fatty acids: contain no double bond

Unsaturated fatty acids: contain one or more double bonds (cis) → bending, decreases melting temperature (liquid at room temperature, increased fluidity)

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22
Q

Naming fatty acids:

A

Length of carbon chain (beginning with carboxyl carbon as 1), and number of double bonds (+ position of double bonds)

Omega = end closest to methyl group

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23
Q

________ and _________ are dietary essential fatty acids because human cells do not have enzyme to introduce double bonds between carbon _____ and _______ end of fatty acids

A

Linoleic acid (omega 6) and Linolenic acid (omega 3)

carbon 9 and omega end

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24
Q

Linoleic acid → ?

Linolenic acid → ?

A

Linoleic acid → precursor for arachidonic acid (PG synthesis)
Linolenic acid → important for growth and development

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25
Q

Palmitate

A

16 chain carbon chain synthesized from Malonyl CoA by Fatty Acid Synthase

Fatty acids synthesized 2 carbons at a time

First two carbons taken from acetyl CoA (not malonyl CoA) and the rest are from malonyl CoA

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26
Q

Elongation and desaturation of fatty acids occurs where and how?

A

Elongation → in mitochondria and ER by Fatty Acid Elongase

Desaturation (introduction of cis double bonds) → in ER by mixed function oxidase

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27
Q

Mitochondrial acetyl CoA produced from oxidation of _________ and catabolism of _________, _________ and __________

A

oxidation of pyruvate and catabolism of fatty acids, ketone bodies, and some AAs

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28
Q

High levels of ________ inhibit _________ allowing _______ to build up in the cytosol of ________ or _______ cell, promoting lipogenesis

A

ATP inhibits TCA cycle

build up of citrate in cytosol of hepatocyte or muscle

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29
Q

Regulation of Acetyl CoA Carboxylase (ACC)

4 main regulators

A

1) Citrate (cytosol) → activate ACC by polymerizing the enzyme and increasing Vmax
2) Fatty acid CoA (Palimitoyl CoA, long chain fatty acid) –> depolymerize ACC → inhibition of ACC (starvation or high fat diet)
3) Insulin → fatty acid synthesis by activating protein phosphatase → dephosphorylates ACC (ACTIVATES enzyme)
4) Glucagon → increase cAMP → activate protein kinase → phosphorylate ACC (INACTIVATE enzyme)

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30
Q

Metabolic regulation of fatty acid synthesis:

High carb –> ?

High fat, low carb –> ?

High insulin –>

High glucagon –> ?

A

1) High carb → HIGH PYRUVATE and ACETYL COA levels in mitochondria → translocation of CITRATE from mitochondria → cytosol → stimulate fatty acid synthesis
2) High fat, low carb → LOW PYRUVATE flux into mitochondria, ELEVATED ACYL COA from fat metabolism in cytoplasm → reduced fatty acid biosynthesis
3) High insulin → fatty acid biosynthesis
4) High glucagon → lipolysis (B-oxidation)

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31
Q

Long-term regulation of fatty acid synthesis

A

prolonged consumption of excess calories → increase transcriptional expression of acetyl CoA carboxylase and fatty acid synthase

Fasting → reduced expression of acetyl CoA carboxylase and fatty acid synthase

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32
Q

Fatty acids are stored as _________

A

Triacylglycerols (TAGs)

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33
Q

Synthesis of TAGs:

In liver vs. in other tissues

A

In liver and adipose tissues: glycerol-3-phosphate made from glucose via glycolysis

In liver only: glycerol kinase directly phosphorylates glycerol to produce glycerol-3-phosphate

Activated fatty acids added to glycerol-3-phosphate

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34
Q

Storage of TAGs

A

TAGs made in liver → packaged with cholesterol, phospholipids, and apoB-100 → VLDL particles secreted into blood → coalesce with adipocytes

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35
Q

Fatty liver disease

A

results from chronic alcoholism typically

Occurs when anabolic and uptake pathways for triacylglycerol in liver increase and/or catabolic or secretion pathways decrease

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36
Q

How ethanol causes hyperlipidemia:

A

Ethanol → acetyl CoA (in liver) → Fatty acids + NADPH

High NADH concentration → DHAP → Glycerol-3-P

Glycerol-3-P + fatty acids → triglyceride

Liver secretes abnormally high levels of VLDLs and eventually chronic liver dysfunction impairs protein synthesis (can’t make ApoB-100)
→ Liver unable to produce VLDL → hepatic fat build up

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37
Q

Fatty acid oxidation:

under ________ conditions, fatty acids are released from _________ by ___________ –> fatty acids brought to ______ or ______

–> degraded by B-oxidation –> ________, ________ and __________

A

Under starvation conditions:

fatty acids released from triacylglycerols (TAGs) by hormone sensitive lipases → fatty acids brought to liver/muscle → degraded by B-oxidation → FADH2, NADH, and acetyl CoA (can generate 12 ATP via TCA cycle)

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38
Q

Main steps of fatty acid oxidation (3)

A

1) Release of fatty acid from triacylglycerols (TAGs)
2) Transport of fatty acids into mitochondrial matrix
3) Repeated cycles of oxidation: Beta-Oxidation

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39
Q

Release of fatty acids from triacylglycerols (TAGs) by what and how?

A

Initiated by hormone sensitive lipase (HSL) → removes fatty acid from carbon 1 and/or 3 of TAG
→ release of FAs and glycerol

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40
Q

Transport of fatty acids into mitochondrial matrix:

1) Fatty acids –> ________ in _________
2) Fatty acid degradation then occurs in the _________ and in order to do this, ____________ must be transported by ______________.

____________ can diffuse into matrix without carnitine.

A

Fatty acids → Acyl CoA in cytosol

Fatty acid degradation occurs in MITOCHONDRIA, BUT LONG CHAIN ACYL CoA molecules

temporary transfer carnitine and transport via carnitine palmitoyl transferase I (CPT-I)

short/medium chain FAs

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41
Q

carnitine palmitoyl transferase I (CPT-I)

A
  • Long chain acyl (fatty acid) group transferred temporarily to carnitine via carnitine palmitoyl transferase I (CPT-I) and transported into mitochondrial matrix
  • RATE LIMITING STEP in B-oxidation
  • Allosterically inhibited by malonyl CoA (high when fatty acid synthesis is active)
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42
Q

4 steps of Beta oxidation

1) _________ (enzyme) uses ______ to oxidize acyl CoAs to introduce a _____ double bond
2) _________ adds water across trans double bond
3) ___________ generates B-keto acyly-CoA and ________
4) ___________ releases acetyl CoA from fatty acid chain and prepares fatty acid chain for another roung od B-oxidation

A

1) Acyl CoA Dehydrogenase (4 forms depending on length of carbon chains in fatty acid), FAD, trans double bond
2) Enoyl CoA Hydratase
3) B-Hydroxy-CoA Dehydrogenase, NADH
4) Thiolase

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43
Q

Beta oxidation occurs in the __________ of cells

A

mitochondria

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44
Q

Oxidation of odd number chain fatty acids:

Last round of oxidation leaves a fatty acyl CoA with 3 carbons…

1) __________ adds a carboxyl group to the fatty acid → ______________
2) D methylmalonyl CoA → _____________ by ______________
3) L Methylmalonyl CoA → _________ by _____________ (requires ____ cofactor) → enters TCA cycle

A

1) Propionyl CoA carboxylase adds a carboxyl group to the fatty acid → D-methylmalonyl CoA
2) D methylmalonyl CoA → L methylmalonyl CoA by methylmalonyl CoA racemase
3) L Methylmalonyl CoA → succinyl CoA by methylmalonyl CoA mutase (requires B12 cofactor) → enters TCA cycle

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45
Q

Deficiency of methylmalonyl CoA mutase or B12

A

causes methylmalonic acidemia and aciduria because of propionate and methylmalonate accumulation in cells

mutase responsible for conversion of L Methylmalonyl CoA → succinyl CoA

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46
Q

Peroxisomal B-oxidation

A

Peroxisomes major site of B-oxidation

Very long chain/branched fatty acids are preferentially oxidized in peroxisomes

Medium chains fatty acids exported from peroxisomes → mitochondria for further oxidation

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47
Q

Zellweger syndrome

A

x linked adrenoleukodystrophy due to defects of peroxisomal B-oxidation

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48
Q

Regulation of Fatty Acid Oxidation: 2 main points of regulation

A

Hormone Sensitive Lipase (HSL)

Carnitine palmitoyltransferase I (CPT-I)

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49
Q

Hormone Sensitive Lipase (HSL)

regulation:

  • active when…
  • inactive when…
A

Responsible for release of fatty acids from TAGs

Active when phosphorylated by cAMP dependent protein kinase (binding of epinephrine → activate AC)

Inactive when dephosphorylated by high insulin/glucose

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50
Q

Carnitine deficiency

A

Carnitine needed for CPT-I transport of long chain acyl CoA into mitochondria for B-oxidation

genetic disorder that results in massive amounts of TAG deposits in liver

→ muscle cramping, hypoglycemia, weakness, death

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51
Q

Ketogenesis occurs in the ___________ of a cell

A

mitochondria

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52
Q

Key steps of ketogenesis (4)

A

1) Formation of acetoacetyl CoA
2) Mitochondrial HMG CoA synthase: acetyl CoA + acetoacetyl CoA → HMG CoA
3) HMG CoA → acetoacetate + acetyl CoA
4) Acetoacetate → 3-hydroxybutyrate + NAD or Acetoacetate → acetone

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53
Q

Ketogenesis:

Formation of acetoacetyl CoA

A

2 acetyl CoA → acetoacetyl CoA

Via reversal of thiolase reaction of fatty acid oxidation

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54
Q

Mitochondrial HMG CoA synthase

A

acetyl CoA + acetoacetyl CoA → HMG CoA

Rate limiting step in ketogenesis

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55
Q

Ketogenesis

HMG CoA –> _________ + _________ via _________

A

HMG CoA → acetoacetate + acetyl CoA

Via HMG CoA lyase

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56
Q

Acetoacetate can go down 2 different paths to generate a ketone body. What are they?

A

Acetoacetate → 3-hydroxybutyrate + NAD
-High levels of NADH during fatty acid oxidation promotes conversion of acetoacetate → 3-hydroxybutyrate

OR

Acetoacetate → acetone

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57
Q

_________ and _________ are ketone bodies

A

Acetone and 3-hydroxybutyrate = KETONE BODIES

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58
Q

Use of Ketone Bodies:

Ketone bodies are primarily produced in the _______, but in order to be used, they must…

A

LIVER

→ diffuse in blood to peripheral tissues and act as primary fuel source for muscle and brain (and other tissues if glucose is low)

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59
Q

Once ketone bodies are in the blood stream what happens to them?

A

**3-hydroxybutyrate converted to acetyl CoA

3-hydroxybutyrate → acetoacetate + NADH → Acetoacetyl CoA (addition of CoA from succinyl CoA) → 2 Acetyl CoA
→ enters TCA cycle for energy

**Acetone eliminated
-Acetone only produced in small amounts
Eliminated in urine or breath

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60
Q

NADH role in regulation of ketogenesis

A

elevated NADH during fatty acid oxidation → inhibit TCA cycle enzymes → accumulation of acetyl CoA → ketone body synthesis

NADH inhibits pyruvate dehydrogenase, activates pyruvate carboxylase

NADH favors formation of 3-hydroxybutyrate

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61
Q

Ketoacidosis

A

extremely high levels of ketone bodies released during periods of extreme metabolic stress

Rate of ketone body formation > rate of use → [ketone bodies] rises in blood and then urine

both ketones are acids, so cause acidosis when elevated in the blood

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62
Q

Type 1 diabetes and ketoacidosis

A

lack insulin → hormone sensitive lipase highly activated → release large quantities of fatty acids from adipose

→ Fatty acid oxidation (produces lots of NADH) → inhibit TCA cycle

→ Excess acetyl CoA generated from fatty acid oxidation → ketone body formation

Ketone bodies are moderately strong acids → lower blood pH → metabolic ketoacidosis

Acetone = highly volatile (“fruity odor”)

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63
Q

Sources of cholesterol in the liver (4)

A

1) Diet (only about 300-600 mg)
2) Enterohepatic circulation (bile acid recycling)
3) Synthesis (about 1g per day)
4) LDL and HDL cholesterol returned from circulation

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64
Q

Major ways HMG CoA Reductase is regulated (3)

A

1) Transcriptional regulation
- Sterol Regulatory Element Binding Protein (SREBP)
- Glucagon, insulin

2) Translational regulation
3) Degradation and phosphorlyation

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65
Q

When cholesterol is present in excess how is HMG CoA Reductase regulated via TRANSCRIPTIONAL changes

A

Cholesterol present in excess → DECREASE HMG CoA reductase gene transcription

SREBP binds SCAP and keeps SREBP in golgi –> SREBP does NOT stimulate HMG CoA reductase transcription in nucleus

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66
Q

Effect of glucagon and insulin on HMG CoA Reductase

A

Glucagon DECREASES expression of HMG CoA reductase gene

Insulin INCREASES expression of HMG CoA reductase gene (insulin high in fed state when NADPH high → excess acetyl CoA)

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67
Q

Sterol Regulatory Element Binding Protein (SREBP)

what it does when cholesterol is high vs. low

A

transcription factor that regulates HMG CoA Reductase transcription

Cholesterol low → SREBP released, moves to nucleus to stimulate transcription of HMG-CoA reductase

Cholesterol high –> bind SCAP protein in golgi and NOT stimulating HMG CoA reductase transcription in nucleus

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68
Q

Translational regulation of HMG CoA Reductase

A

Cholesterol in excess → reduce translation of mRNA encoding HMG CoA reductase and decreased mRNA half life

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69
Q

Degradation and Phosphorylation of HMG CoA Reductase

A

Cholesterol in excess → reduce half life of HMG CoA Reductase (11 → 2 hrs) and AMP kinase phosphorylates (inactivates) HMG CoA Reductase

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70
Q

Steps in de novo cholesterol synthesis

A

1) Acetyl CoA → HMG CoA
2) HMG CoA → Mevalonate
3) Mevalonate → Cholesterol

Energy requiring pathway (ATP x2 and NADPH x2) → occurs in fed state

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71
Q

Acetyl CoA –> HMG CoA

catalyzed by what enzymes and where?

A

Catalyzed by thiolase and HMG CoA Synthase

Liver → two isoforms

  • Cytosol → cholesterol synthesis
  • Mitochondria → ketone generation
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72
Q

HMG CoA Reductase

A

HMG CoA → Mevalonate

Key rate limiting step in cholesterol synthesis

Highly regulated

Occurs in CYTOSOL

Uses NADPH as reducing agent

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73
Q

geranyl pyrophosphate and farnesyl pyrophosphate

A

Key intermediates from the cholesterol synthesis pathway

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74
Q

Glycerophospholipids

structure

4 examples

A

make up the bulk of membrane lipids

Structure: [Glycerol] + fatty acid + fatty acid + PO4-alcohol

EX) Phosphatidylserine (PS), Phosphatidylinositol, Phosphatidylethanolamine (PE), Phosphatidylcholine (PC)

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75
Q

Phosphatidylserine (PS)

A

gylcerophospholipid

important for membrane synthesis

Synthesized by base exchange reaction

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76
Q

Phosphatidylinositol

A

gylcerophospholipid

Important in signal transduction

Reservoir for arachidonic acid (PG synthesis)

Important membrane protein anchoring

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77
Q

Phosphatidylethanolamine (PE)

A

gylcerophospholipid

one of most abundant phospholipids in the body

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78
Q

Phosphatidylcholine (PC)

A

gylcerophospholipid

one of most abundant phospholipids in the body

Main component of lung surfactant and in bile

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79
Q

Sphingomyelin

structure

where in the body is it located primarily?

A

sphingolipid

Structure: [sphingosine] (aka ceramide) + fatty acid + PO4-Choline

Major structural lipid in nerve tissue

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80
Q

Sphingosine

A

backbone component in sphingolipids and glycosphingolipids

built from serine (AA) +fatty acid (palmitate)

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81
Q

Glycosphingolipid

A

Structure: [sphingosine] + FA + mono/oligosaccharide (head group)

Lipids primarily in brain and peripheral nerves

EX) Cerebroside, globoside, ganglioside

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82
Q

Synthesis of Glycerophospholipids

A

how they acquire their headgroups

Backbone comes from phosphatidic acid (precursor to triglyceride biosynthesis) then polar head group is added

PC and PE head groups formed de novo or come from diet → activated by CPD then attached to backbone

“Base exchange” = head groups exchanged onto previously synthesized phospholipids

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83
Q

Synthesis of arachidonic acid and prostaglandins

A

Synthesized from dietary fat (linoleic acid) → converted to arachidonic acid → prostaglandin (COX enzyme) or leukotrienes (5-lipoxygenase enzyme)

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84
Q

Five classes of lipoproteins

A

1) Chylomicrons
2) VLDL
3) Remnant particles (IDL)
4) LDL
5) HDL

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85
Q

Chylomicrons

A

made by GI tract from dietary fat

10:1 triglyceride > cholesterol

Responsible for rise in triglyceride level after meals

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86
Q

Very Low Density Lipoproteins (VLDL)

A

5:1 triglyceride > cholesterol

Made by liver –> Deliver triglyceride to peripheral tissue between meals

Source of basal triglyceride production

Decreased production post-meal

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87
Q

Remnant particles and Intermediate Density Lipoproteins

A

Metabolic byproducts of metabolism of chylomicrons and VLDL

Relatively CHOLESTEROL ENRICHED after TG delivered to peripheral tissues (tri=cholesterol)

Taken up by liver via remnant receptor

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88
Q

Low Density Lipoproteins (LDL)

A

produced from metabolism of VLDL

Cholesterol > TG → very atherogenic (more dense, smaller, the more atherogenic)

Cleared from circulation by liver via uptake by LDL receptor

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89
Q

High Density Lipoproteins (HDL)

A

“Trash trucks” of lipid metabolism

Collect cholesterol form peripheral tissues and transport it back to liver

Reservoir of phospholipids for other lipoprotein particles

Can exchange triglyceride and apo-proteins with other particles in circulation

Anti-atherogenic

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90
Q

Chylomicron pathway

1) In the small intestine, triglycerides are broken down by _______ into ________ and __________
2) Lipids then diffuse/transported across intestinal wall
3) _______ are RE-synthesized and packaged into ________ with apo_______

A

1) Triglyceride → monoacylglycerol + free fatty acids
by LIPASE

2) Lipids diffuse/transported across intestinal wall
3) Triglycerides RE-synthesized and packaged into chylomicrons with apoprotein B48

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91
Q

Chylomicron pathway

4) Chylomicrons are secreted in ______ –> enter central circulation –> acquire apo_____ and _______ from _________
5) TG in chylomicron broken down by _________ at endothelial surface of ______ and _______ tissues

**this enzyme requires _______ as a cofactor!

6) Results in production of ___________ –> taken up by liver by _______ receptors

A

4) Chylomicrons secreted in LACTEALS (gut lymphatics) → enter central circulation → acquire apoproteins *C-2 and *E from *HDL
5) Triglyceride in chylomicron broken down by LIPOPROTEIN LIPASE (LPL) at endothelial surface of MUSCLE AND ADIPOSE

LPL requires apoprotein C-2** as cofactor

6) Results in production of chylomicron-remnant particles → taken up by liver by remnant receptors (remnant particles not present in fasting state)

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92
Q

Without apo-C-2 on chylomicrons what happens?

A

No C-2 → no triglyceride breakdown by LPL → hypertriglyceridemia

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93
Q

VLDL pathway

1) VLDL secreted from _______ with apo ______ attached
2) VLDL acquires apo ______ and apo ______ from ________ in peripheral circulation
3) VLDL metabolized by ______ → ________
4) ______ cleared from body by ________ via endocytosis into ___________

**apo ______ is a cofactor for the LDL receptor, so LDL particles must have apo ______ on them in order to be cleared

A

1) Secretion of VLDL from liver with apoB100
2) VLDL acquires apoprotein C-2* and apolipoprotein E* from HDL* in peripheral circulation
3) VLDL metabolized by LPL –> LDL
4) LDL cleared from body by LDL receptor via endocytosis into LIVER

**apo B100 is a cofactor for the LDL receptor, so LDL particles must have apo B100 on them in order to be cleared

94
Q

HDL pathway

1) HDL contains apo ______ which allows HDL to circulate in plasma and pick up _________
2) HDL can pick up free cholesterol in tissues via ________ or ________ which requires help from __________

A

1) HDL contains apo A1 which allows HDL to circulate in plasma and pick up FREE CHOLESTEROL
2) HDL can pick up free cholesterol in tissues via DIFFUSION or FACILITATED TRANSPORT which requires help from ABC-A1 CASSETTE

95
Q

HDL pathway

3) Free cholesterol on HDL is “trapped” in particle by conversion to _________ by ___________
4) _____________ allows maturing HDL particle to transfer cholesterol esters to VLDL in exchange for triglycerides
5) HDL also serves as reservoir for apo____ and _____ which it can donate to ______ and _______

A

3) Free cholesterol on HDL is “trapped” in particle by conversion to CHOLESTEROL ESTER (less polar) by lecithin cholesterol acyltransferase (LCAT)
4) Cholesterol ester transfer protein (CTEP) allows maturing HDL particle to transfer cholesterol esters to VLDL in exchange for triglycerides
5) HDL also serves as reservoir for apo C2 and E which it can donate to VLDL and Chylomicrons

96
Q

Apolipoproteins act as…(3)

A

1) Structural scaffold backbone of lipoprotein particle
2) Enzymatic cofactors/regulators
3) Ligands for receptors

97
Q

Apolipoproteins that act as structural scaffold backbone of lipoprotein particle

(3)

A

ApoB48 → chylomicrons

ApoB100 → VLDL and LDL

ApoA1 → HDL

98
Q

Apolipoproteins that act as enzymatic cofactors/regulators

A

ApoC2 → cofactor for LPL

ApoC3 → inhibits LPL

99
Q

Apolipoproteins that act as ligands for receptors

A

ApoB100 → ligand for LDL receptor

ApoE → ligand for remnant receptor

100
Q

Cholesterol ester transfer protein (CETP)

A

Allows maturing HDL particle to transfer cholesterol esters to VLDL in exchange for triglycerides

Occurs when tg levels are high, provides alternate route of tg clearance

101
Q

ABC-A1 cassette

A

ATP binding cassette (ABC) transporter

Important in transport of cholesterol from peripheral tissues to apo A-1 (core apoprotein of HDL)

102
Q

Lecithin cholesterol acyltransferase (LCAT)

A

Lecithin cholesterol acyltransferase
Transfers fatty acid from phospholipid onto free cholesterol → esterified cholesterol, that is more nonpolar and more tightly bound to HDL

103
Q

Tangiers disease

A

lack ABCa1 protein → unable to remove cholesterol from peripheral tissues → very low HDL levels, premature atherosclerosis (“orange tonsils” due to accumulation of cholesterol in lymphatics)

104
Q

LCAT deficiency

A

low levels of HDL, corneal opacities, renal insufficiency, hemolytic anemia due to accumulation of unesterified cholesterol in tissues

105
Q

Exercise and fat/carb usage by skeletal muscle as intensity increases

A

1) When exercise begins glucose is the primary fuel
2) Then with sustained low intensity exercise, fat oxidation predominates
3) As intensity increases glucose oxidation predominates
4) As intensity increases further, anaerobic metabolism predominates and lactate production increases

106
Q

Fat oxidation vs. carbohydrate oxidation and exercise

A

At low exercise intensities, fat is preferred substrate (although always some glucose oxidation)

Oxidation of fat yields more ATP than CHO, but ATP synthesis from CHO is much faster

**The point at which you switch off fat oxidation and go to CHO increases the more trained you are

Once glycolysis is in action, lactate levels continue to rise until a certain point and you stop exercising

107
Q

Epinephrine and exercise

A

released from adrenal medulla, release is directly proportional to exercise intensity

→ stimulates glycogenolysis

→ stimulates hormone sensitive lipase (increasing availability of free fatty acids (FFA) during exercise

HOWEVER at very high exercise intensity, there is vasoconstriction of vessels going to fat → less lipolysis

108
Q

Insulin and exercise

A

Insulin → inhibit lipolysis at rest, but during exercise, insulin secretion falls → higher lipolytic activity

109
Q

Adaptations with training (5)

A

can go backwards when you become inactive

1) Increased muscle mass
2) Increased mitochondrial content/oxidative capacity per gram of muscle
3) Increased intramuscular glycogen and triglyceride from increased turnover
4) Increased rates of lipolysis, beta oxidation and lactate clearance
5) Result is increased work capacity and shift to fat as the preferred fuel

110
Q

People with diabetes, and inactivity results in __________ mitochondria and mitochondrial function

A

REDUCED

More mitochondria → increases insulin sensitivity in diabetic

–> exercise beneficial for diabetics (exercise also increases glucose transport into cell)

111
Q

Training adaptations to substrate utilization: (3)

A

1) Decreased glycolytic flux at same relative intensities (decrease in glycogenolysis, lower glucose utilization)
- Reduced energy requirements derived from glucose

2) Lower blood lactate accumulation after training
3) Higher fat utilization: point you switch from fat oxidation back to glycolysis pushed farther out the more trained you are

112
Q

Lower blood lactate accumulation after training

why?

A

1) Increased mitochondrial density → increased lactate clearing capacity
2) Increased MCT1 and MCT 4 expression for increased lactate transport

113
Q

Metacarboxylates (MCTs)

A

specific lactate transporters, facilitate lactate transport in and out of muscle cell

MCT1 and MCT4

114
Q

MCT1

A

oxidative muscle fibers (type I)

Transport inside cell and into mitochondria

Endurance training increases MCT1 expression → higher lactate clearance

115
Q

MCT4

A

in glycolytic fibers (type II)

Lactate transport out of cell from glycolytic fibers to more oxidative fibers

Endurance training increases MCT4 expression → higher lactate transport to oxidative cells

116
Q

Symptoms of Hypoglycemia

2 types of symptoms

A

ANS activation

Neuroglycopenic symptoms

*Can injure developing brain and result in permanent developmental problems

117
Q

ANS activation symptoms of hypoglycemia

A

Sweating, shaking, trembling, tachycardia, anxiety, weakness, hunger, nausea, vomiting

118
Q

Neuroglycopenic symptoms of hypoglycemia

A

Irritable, restless, headache, confusion, visual changes, slurred speech, impaired concentration, behavior changes, somnolence, coma/seizures

119
Q

If hypoglycemia onset occurs after < 4-6 hours what are the possible causes? (4)

A

1) Glucose-6-Phosphatase deficiency
2) Glycogen storage diseases
3) Hyperinsulinism
4) Cortisol or GH deficiency in infants

120
Q

If hypoglycemia onset occurs after >6-8 hours what are the possible causes? (4)

A

1) Cortisol and GH deficiency in infants, children, and adults
2) Fatty acid oxidation disorders in infants
3) Glycogen storage diseases
4) Gluconeogenic diseases

121
Q

If hypoglycemia onset occurs after >10-12 hours what are the possible causes? (2)

A

1) Fatty acid oxidation disorders in older children and adults
2) Mild disorders of glycogen storage in adults

122
Q

If hypoglycemia onset occurs after >12-24 hours what are the possible causes? (2)

A

1) Ketotic hypoglycemia (not actually a disorder, just when you are really skinny and don’t have lots of reserves)
2) Fatty acid oxidation disorders in older children and adults

123
Q

If you are having problems with carbohydrate metabolism, but not fat metabolism what will be the clinical picture? (5 + possible precipitating events)

A

1) Ketones PRESENT (look at lower bicarb for ketones)
2) High uric acid → glucose trying to get out of liver
3) High triglycerides → glucose trying to get our of liver
4) Hypoglycemia
5) Accumulation of abnormal amounts of substrate behind block

Precipitating factors: fasting, illness, exercise, ingestion of dietary galactose or fructose

124
Q

Glucose-6-Phosphatase deficiency: Von Gierke Disease

A

Most severe glycogen storage disease

Glucose enters liver normally, but cannot produce free glucose to leave liver → alternate pathways to get out

Lactate production, increased fatty acid synthesis (hypertriglyceridemia) and increased uric acid due to shunting and decreased renal excretion

Can make glycogen in liver, but cannot leave liver as glucose
→ Dramatic enlargement of liver (accumulation of NORMAL glycogen)

125
Q

Presentation of Glucose-6-phosphatase deficiency (5)

A

infants within first year of life with SEVERE fasting hypoglycemia occurring within *3-4 hours after a meal

1) Enlargement of liver
2) Hypertriglyceridemia
3) Increased uric acid
4) Increased lactate production
5) Severe hypoglycemia

126
Q

Treatment of Glucose-6-phosphatase deficiency

A

constant glucose supply

127
Q

Glycogen synthase deficiency

A

cannot make glycogen, so nowhere to store glucose after a meal

Solely dependent on gluconeogenesis for glucose production

128
Q

Glycogen synthase deficiency

presentation (2)

A

1) Hyperglycemia after a meal → fasting hypoglycemia
→ increased lactate, severe ketotic hypoglycemia
2) NO liver enlargement

129
Q

Treatment of Glycogen synthase deficiency

A

high protein diet (gluconeogenic substrate) and low glycemic index carbs to minimize postprandial hyperglycemia

130
Q

Branching enzyme deficiency

A

abnormal glycogen that is not branched

Accumulation in liver and skeletal muscle → tissue damage

131
Q

Branching enzyme deficiency

presentation (5)

A

1) Hypoglycemia NOT a prominent symptom - TISSUE DAMAGE IS
2) Progressive liver cirrhosis, hepatosplenomegaly
3) Failure to thrive
4) Neonatal hypotonia and muscle weakness
5) Neuropathy

132
Q

Glycogen phosphorylase deficiency and phosphorylase kinase deficiency:

A

Milder than G-6-phosphatase deficiency

Problem with glycogen breakdown

Gluconeogenesis, lipolysis, fatty acid oxidation, and ketogenesis intact

133
Q

Glycogen phosphorylase deficiency and phosphorylase kinase deficiency:

presentation (4)

A

Ketotic hypoglycemia
Hepatomegaly
Short stature
Mild muscle weakness

134
Q

Debranching enzyme deficiency (Cori Disease)

A

accumulation of abnormal glycogen in liver and muscle

problem with unbranching of stored, branched, glycogen

135
Q

Debranching enzyme deficiency (Cori Disease)

Presentation:
Infants have ________ and ________ BUT their _______ and ________ levels are normal

Later in life, symptoms are milder and can be _________, _________, or ___________

A

Infants with hepatomegaly and hypoglycemia
-Lactate and uric acid levels normal

Later in life, symptoms are milder:
Hepatomegaly
Growth/short stature
Myopathy

136
Q

Fructose-1,6-bisphosphatase deficiency

A

late hypoglycemia following fasting for 18-24 hours

Glycogen formation and breakdown are normal

Elevation of ketones during hypoglycemia (no defect in fat oxidation)

Can be precipitated by ingestion of fructose

137
Q

Fructose-1,6-bisphosphatase deficiency

presentation (3)

A

1) Hypoglycemia (late and mild) - late hypoglycemia following fasting for 18-24 hours
2) Glycogen breakdown OK, no hepatomegaly
3) Elevated pyruvate → severe lactic acidosis → compensatory respiratory alkalosis (hyperventilation)

138
Q

Fructose-1,6-bisphosphatase deficiency

treatment

A

give glucose through diet

139
Q

Hereditary fructose intolerance mechanism

what accumulates? what does this accumulation inhibit?

A

Fructose → fructose-1-P by fructokinase → split into 3 carbon compounds by aldolase B → enter glycolysis/gluconeogenesis BELOW PFK1

Get accumulation of F-1-P → inhibits glycogenolysis and gluconeogenesis → hypoglycemia

140
Q

Hereditary fructose intolerance mechanism

presentation (4)

A

Symptoms arise after fructose ingestion (e.g. fruit)

Nausea, vomiting, pallor, coma

Hypoglycemia

Hepatomegaly, elevated liver function tests (can progress to liver/kidney problems)

141
Q

Galactosemia

mechanism

A

galactose → galactose-1-P → UDP-galactose → UDP glucose

Deficiency in enzyme that produces UDP galactose
Galactose-1-Phosphate Uridyltransferase (GALT)

Unable to metabolize galactose (e.g. from milk)

142
Q

Galactosemia presentation

A

Early failure to thrive (vomiting with milk)

Hepatomegaly, cirrhosis

Cataracts, visual impairment (galactose in lens of eye)

Mental retardation

Neurologic problems (ataxia, tremor, speech impairment)

143
Q

Treatment of galactosemia

A

lactose-free diet

144
Q

Decreased fatty acid oxidation and ketone formation general presentation

A

1) Fasting hypoglycemia with LOW KETONES
2) Liver failure
3) Hypotonia
4) Coagulopathy
5) Hyperammonemia (increased AA breakdown)
6) Elevated CK (from exercise induced rhabdomyolysis)

145
Q

Medium chain acyl CoA dehydrogenase deficiency (MCAD)

A

Unable to complete beta-oxidation for medium chain fatty acids

→ skeletal muscle increased reliance on glucose → increased peripheral glucose utilization

No energy from fatty acid oxidation for gluconeogenesis → reduced gluconeogenesis in liver
→ accumulation of carbon skeletons from gluconeogenic precursors → urinary organic acids

Reduced production of acetyl CoA by B-oxidation → failure to produce ketone bodies

146
Q

Medium chain acyl CoA dehydrogenase deficiency (MCAD)

Presentation (6)

A

1) Infancy/early childhood - moderately severe hypoglycemia after 12-18 hours of fasting (especially with viral illness)
2) Abnormal urinary organic acids
3) Increase in acyl CoA derivatives in blood and urine
4) Decreased carnitine and increased acylcarnitines in blood
5) Hepatomegaly (fatty liver)
6) Hypoketotic hypoglycemia

147
Q

MCAD treatment

A

avoid fasting, low fat, high carb diet

148
Q

Very long chain acyl CoA dehydrogenase deficiency (VLCAD)

A

Similar phenotype to MCAD but may be milder and appear later in life
May get muscle soreness or rhabdomyolysis after exercise

149
Q

CPT-1 Deficiency

A

carnitine problem

CPT-1 required to carry fatty acids into mitochondria where beta-oxidation takes place

No CPT-1 → defect in fat oxidation → fasting hypoglycemia with low levels of ketones

150
Q

CPT-1 Deficiency presentation (3)

A

Presents in infancy following viral illness
Increased levels of free carnitine, low levels of acyl-carnitines
Elevated ammonia

151
Q

Other medical causes of hypoglycemia (7)

A

1) Deficient counterregulatory hormones: glucagon, cortisol, growth hormone, or epinephrine deficient
2) Hyperinsulinism (transient, prolonged, permanent)
3) Ketotic hypoglycemia
4) Insulinoma
5) Insulin overdose
6) Sulfonylurea ingestion
7) Ethanol ingestion

152
Q

___________ or __________ can cause counterregulatory hormone deficiency and hypoglycemia

A

hypopituitarism

adrenal insufficiency

153
Q

Hypopituitarism

A

→ ACTH and/or GH deficiency

Midline defects, micropenis/undescended testes, jaundice, nystagmus, poor growth

154
Q

Adrenal insufficiency

A

→ cortisol deficiency

Poor growth/weight, decreased energy, nausea, vomiting, abdominal pain, hypotension, salt craving, hyperpigmentation, other autoimmune diseases

155
Q

Hyperinsulinism

possible causes

A

Transient, prolonged, or permanent

Causes: maternal diabetes, IV glucose given to mother during labor, perinatal stress, congenital hyperinsulinism

156
Q

Infants of diabetic mothers

A

Large for gestational age (LGA) due to excessive maternal glucose and AA crossing placenta (maternal insulin does not) → EXCESSIVE INSULIN SECRETION by fetal pancreas in third trimester

→ HYPOGLYCEMIA after birth → excessive IV infusion required after birth and absence of ketones in blood

157
Q

Ketotic hypoglycemia

A

Most common cause of hypoglycemia in childhood

Limited stores of muscle protein → cannot sustain normoglycemia from gluconeogenesis during periods of acute illness and reduced food intake

158
Q

Ketotic hypoglycemia

presentation

A

Thin, undernourished (15 months - 5 years)

Enhanced ketone production (elevated serum/urine ketone)

“Grow out” of it as muscle mass increases and glucose utilization decreases

159
Q

Insulinoma

A

tumor of endocrine pancreas

Condition of adults (not children)

Associated with Multiple Endocrine Neoplasia type I (MEN1)

High insulin + hypoglycemia + C-peptide + low ketones (insulin inhibits ketogenesis)

160
Q

Insulin overdose

A

No serum c-peptide elevation with elevated insulin levels

161
Q

Lab evaluation of hypoglycemia

A

obtain blood/urine BEFORE treatment has begun - “critical samples” collected at time of hypoglycemia

162
Q

Increase risk of CVD with which lipid abnormalities?

A
  1. High LDL-C → biochemical modification and resultant inflammation and atherosclerosis → consistently increased risk of CVD
  2. High triglycerides:
    - *NO evidence that lowering triglycerides improves CVD
  3. Low HDL-C: linked to increased risk for CVD
    - Increasing HDL with drugs has NO benefit for CVD
  4. High Non-HDL-C:
163
Q

Non HDL-Cholesterol =

A

Non HDL-Cholesterol = Total Cholesterol - HDL

a. Includes all apoB-100 containing lipoproteins (VLDL, IDL, LDL)
2. Thought to possibly be better predictor of ASCVD than LDL

164
Q

Total cholesterol = ___ + ____ + _____

A

HDL + LDL + VLDL

165
Q

Estimation of VLDL

A

When fasting, VLDL = TG/5 (as long as triglycerides are < 400 mg/dL)

166
Q

Calculation of LDL-C

A

Friedewald Formula: LDL-C = Total cholesterol - HDL - TG/5

167
Q

Risk factors for atherosclerotic events: (7)

A
  1. Age, males > females
  2. Caucasian vs. African American
  3. Higher total cholesterol
  4. Lower HDL
  5. Current cigarette smoking
  6. Systolic BP > 140 or anti-HTN medications
  7. Diabetes
168
Q

Risk estimator

A

calculates score for 10-year ASCVD risk and Lifetime ASCVD risk

169
Q

Causes of increased LDL

A

Increased LDL production or decreased catabolism

170
Q

Increased LDL-C Production:

A

overproduction of VLDL by liver

E.g. insulin resistance

171
Q

2 diseases that cause decreased LDL catabolism

A
  1. Familial hypercholesterolemia (FH)

2. Gain of function mutation in PCSK9

172
Q

Familial hypercholesterolemia

A

AD absence/defectiveness of LDL receptor → LDL 2-3x normal in heterozygotes and 5-8x normal in homozygotes

173
Q

PCSK9

A

regulator of LDL receptor degradation - PCSK9 binds LDL receptor and signals its degradation

174
Q

Loss of function mutation in PCSK9

A

increased LDL receptor function, low LDL, reduced ASCVD

175
Q

Gain of function mutation in PCSK9

A

clinical FH, reduced LDL receptor activity

176
Q

Physical exam findings in hypercholesterolemia (3)

A
  1. Arcus cornealis: lipid deposits at limbus of cornea
  2. Xanthelasmas: lipid deposits in skin of eyelid
  3. Tendinous xanthomas: typically involves achilles tendons and extensor tendons of the hands
177
Q

Normal tryglyceride level

A

Normal is < 150 mg/dL,

178
Q

Triglyceride level 150-300 →

A

increased ASCVD

179
Q

Triglyceride level 500-1000 →

A

clearance of chylomicrons approaches saturation

180
Q

Triglyceride level > 1000 →

A

serum becomes lipemic

181
Q

PE findings of high triglycerides (4)

A
  1. Lipemia retinalis: fatty serum in small vessels of retina
  2. Eruptive xanthomas: small yellowish papules on extensor surfaces of arms, abdomen, and back
  3. Hepatosplenomegaly (from triglyceride infiltration)
  4. Abdominal pain +/- acute pancreatitis
182
Q

Increased VLDL production (4)

A
  1. Insulin resistance → increases in free fatty acid flux from adipose tissue
    - Insulin is ANTI-lipolytic, so with insulin resistance more FFAs are released, go to liver, and increase hepatic VLDL synthesis and secretion
  2. Drugs (See above)
  3. Alcohol: inhibits VLDL secretion, but enhances fatty acid production from ethanol → hypertriglyceridemia
  4. Genetics: Lipoprotein Lipase (LPL) and Apo A5 mutations
183
Q

Decreased Triglyceride-Rich Lipoprotein Catabolism (4)

A

decrease lipoprotein triglyceride metabolism due to decreased lipoprotein lipase activity

1) Deficiency in LPL
2) Deficiency of Apo C2 (activator of LPL)
3) Deficiency in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (anchors LPL to endothelium)
4) Familial Dysbetalipoproteinemia:

184
Q

Familial Dysbetalipoproteinemia

A

disturbances in IDL and remnant catabolism → increases in total cholesterol and triglycerides

Genetic variations in ApoE, ApoE2 isoform → defective binding of apoE2 to hepatic receptors that recognize VLDL and chylomicron remnants

185
Q

Presentation of familial dysbetalipoproteinemia

A

plantas xanthomata, premature atherosclerosis

186
Q

Causes of low HDL-C (4)

A
  1. Tangier disease
  2. Familial HDL deficiency
  3. LCAt deficiency
  4. Familial hypoalphalipoproteinemia
187
Q

Tangier disease

A

genetic cause of HDL deficiency due to mutations in ATP binding cassette protein-1 (ABC-a1)

  • Autosomal co-dominant
  • Manifests as accumulation of cholesterol in peripheral organs with orange tonsils on exam
188
Q

Familial HDL deciciency

A

genetic cause of HDL deficiency due to mutations in ATP binding cassette protein-1 (ABC-a1)

AD, not associated with systemic findings seen in Tangier disease

189
Q

LCAt deficiency

A

homozygous mutations of LCAT gene → very low HDL levels

  1. Corneal opacities (fish eye syndrome)
  2. No increased ASCVD risk
190
Q

Familial hypoalphalipoproteinemia

A

AD disorder, mutations in apoA1 gene

1.Linked to premature ASCVD

191
Q

Apo(a)

A

apolipoprotein linked by a single disulfide bridge to LDL apoB → Lp(a)

  • Increased Lp(a) linked with premature atherosclerosis (especially in women < 55yrs)
192
Q

Mechanism of statins (3)

A

1) HMG CoA Reductase Inhibitors
2) Decrease hepatic pool of free cholesterol

3) Increase expression of LDL receptors on cell membranes
- (increasing uptake and catabolism of circulating LDL)

193
Q

Effects of statins

A

First line, highly effective in lowering LDL and high intensity statin effective in lower triglycerides as well

194
Q

6% rule and statins

A

Majority of LDL lowering comes from starting dose, and 6% reduction in LDL with each doubling of dose

195
Q

Indications for statin therapy (4)

A

a. Secondary prevention (clinical ASCVD)
b. LDL >190, age > 21 years
c. Primary prevention - diabetes, age 40-75, LDL 70-189
d. Primary prevention - no diabetes, > 7.5% 10 year ASCVD risk, age 40-75 years, LDL 70-189

196
Q

Side effects of statins (3)

A

higher risk of complications when combined with other lipid lowering agents (niacin, fibrates)

1) Myopathy: rhabdomyolysis, myositis (elevated CPK), myalgias
2) Abnormal AST and ALT

3) Associated with 10% increased risk of new-onset T2D
- Benefits highly outweigh this risk

197
Q

3 Bile acid sequestrants

A

cholestyramine, colestipol, colesevelam

198
Q

Mechanism of bile acid sequestrants

A

high molecular weight polymers that bind bile acids in intestine in exchange for a chloride ion

a. Neither absorbed nor metabolised
b. Reduce enterohepatic circulation of bile acids → increased LDL receptor expression in liver (use LDL to make bile acid)

199
Q

Bile acid sequestrants lower LDL by ___%

A

10-30%

Statins lower LDL much more and have fewer adverse effects

Used as add on therapy, or if statin not tolerated

200
Q

Side effects of bile acid sequestrants

A
  • GI problems (nausea, bloating, constipation)
  • Can also bind other drugs in gut (warfarin, thyroid hormone)
  • Can raise TG by 5-30%
201
Q

Ezetimibe mechanism

A

selectively inhibits cholesterol absorption at brush border

a.LDL lowering effect via increases in LDL receptor

202
Q

Ezetimibe and statin

A

Improves outcomes by 20% when combined with statin

203
Q

Side effects of ezetimibe (14)

A

NONE

Got ya!

204
Q

Plant sterol and stanol esters

A
  1. No ASCVD data to support use
  2. No side effects
  3. Minimal LDL lowering
205
Q

Mechanism of plant sterol and stanol esters

A

prevent mixed micelle formation in small intestine, partially reducing cholesterol absorption

206
Q

2 PCSK9 inhibitors

A

alirocumab, evolocumab

207
Q

PCSK9 inhibitors

A
  1. Injectable
  2. Lowers LDL by up to 60%
  3. Adjuncts to diet and max statin therapy for treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic CVD who require additional LDL lowering
208
Q

3 classes of triglyceride lowering drugs

A
  1. Fibrates
  2. Fish oil
  3. Niacin
209
Q

2 fibrates

A

gemfibrozil and fenofibrate

210
Q

Fenofibrate

A

induces PPARa-related gene expression → increase intra hepatic fatty acid oxidation and reduce VLDL TG synthesis/secretion

211
Q

Side effects of fenofibrate

A

Can raise creatinine (reversible when drug stopped)

212
Q

When is gemfibrozil contraindicated

A

contraindicated when statins are coadministered due to higher risk of myopathy

a.Increased risk of cholelithiasis

213
Q

Fish oils

A

high dose omega-3 fatty acids lower TG by 15-35%, and slightly increase HDL

  1. No evidence of educed ASCVD
  2. Only approved to treat patients with fasting TG > 500
214
Q

Niacin
___ LDL
___ TG
___ HDL

A

lowers LDL
lowers TG
raises HDL

215
Q

Niacin and statins

A

No additional benefit when used with statins

216
Q

Side effects of niacin

A

flushing, rash, GI distress, hepatotoxicity, myopathy, glucose intolerance, hyperuricemia, gout

217
Q

Primary treatment of elevated LDL-C and triglycerides

A

Statins

218
Q

Secondary treatment of LDL-C and triglycerides

A

bile acid sequestrants, ezetimibe

  1. Can also consider fibrate and/or niacin
    ii. **Combining classes has additive effects
219
Q

Average kcal/kg/day

A

30 kcal/kg/day

KNOW HOW TO CALCULATE THIS STUFF

50kg woman x 30 kcal/kg/day = 1500 kcal/day

220
Q

Traditional American diet consists of:

____% fat (____ % of this is SATURATED fat)

____% protein

_____% carbohydrate

A

33-37% fat, 50% of that is SATURATED fat

15% protein (animal)

48-52% carbohydrate

221
Q

Biggest changes in american diet are: (4)

A

Increased omega-6 fat (corn oil)

Trans fat

Reduced whole grains and fiber

Increased total energy intake (calories), no fasting

222
Q

Pool sizes of stored triglycerides

Adipose, liver/skeletal muscle

A

Adipose tissue: average person adipose tissue is 20-30% their body weight

  • 70 kg person + 25% body fat → 18 kg of triglyceride x 9 kcal/g = 157,000 kcal stored energy
  • 75 days of energy!

Liver and skeletal muscle: small amount of stored triglyceride, (hundreds of grams)

223
Q

Distinguishing saturated and trans fats from unsaturated fats:

A

Saturated fats: form crystals at room temperature, and are therefore solid

Unsaturated fats: have cis double bonds and are typically liquid at room temp

EX) olive oil, nut oils, corn oil

224
Q

Saturated fat:

A

Solid at room temp

Saturated and trans fats have adverse effects on CVD risk and increase risk for diabetes (promotes insulin resistance)

225
Q

Monounsaturated fat

_______ is an example
benefits or adverse effects?

A

Oleic acid (C18 monounsaturated fat): olive oil, canola oil

May reduce risk for CVD, and have beneficial health effects

226
Q

Omega-3 fat

A

(linolenic acid): fish and seafood, nut oils

Protect against diabetes

227
Q

Omega-6 fat

A

(linoleic acid): vegetable and corn oils

Worse health effects than omega-3’s - associated with increased CVD risk

228
Q

what is an example of a polyunsaturated fat

A

Fish oil DHA supplement

229
Q

Trans fat

A

partially hydrogenated corn oil to generate double bonds in trans configuration → body may have trouble metabolizing these fats

Margarine, processed foods

Appear to have the most deleterious effects

230
Q

Best diet or way to reduce CVD risk

A
  • REDUCE positive energy balance
  • Adherance to a diet whatever it is, is key
  • most evidence is for low fat diet
  • Good evidence for Mediterranean diet also

DEMS (10 decks)

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