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Gastro > biochem - lipid metabolism > Flashcards

biochem - lipid metabolism Flashcards

1
Q

functions of lipids

A
  • energy source
  • components of cell membrane (phospholipids)
  • communication molecules (steroid hormones)
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2
Q

why do FAs have even number of carbons

A
  • when synthesized, 2 Cs are added at once by organisms
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3
Q

essential fatty acids in the body

A
  • omega-3 FA (double bond is on 3rd C atom, where C1 is the non-carboxylic end of FA)
  • omega-6 FA
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4
Q

problem with trans fatty acids

A
  • increase LDL, decreases HDL→ atherosclerosis
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5
Q

dietary lipids composition

A

10%
- cholesterol, cholesterol esters, phospholipids, fatty acids

90%
- TAG (triacylglycerol, aka TG triglyceride)

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6
Q

enzymes for digestion of different lipid forms

A

TAG
- digested by lipase (mouth, stomach, pancreas)
- TAG→ diacylglycerol→ 2-monoacylglycerol + 2FA

cholesterol ester
- digested by cholesterol esterase (pancreatic)
- cholesterol ester→ cholesterol + FA

phospholipid
- digested by phospholipase A2 (pancreatic)
- phospholipid→ lysophospholipid/lysolecithin + FA

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7
Q

lipid digestion based on location

A

Stomach
- lingual lipase (mouth) and gastric lipase (stomach): digest triglycerides in the stomach
- lingual lipase is more active in the stomach as it requires low pH

Small intestine
- major site of lipid digestion
- secretion of bile salts and pancreatic lipase/colipase
- emulsification of fats by bile salts to form micelles
- digestion of fats mediated by enzymes (e.g pancreatic lipase, cholesterol esterase and phospholipase A2)
- absorption into enterocytes

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8
Q

function of colipase

A
  • bind to pancreatic lipase & anchors it to micelle
  • remove inhibitory effect of bile salts on pancreatic lipase
  • essentially increases activity of pancreatic lipase
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9
Q

hormones released by small intestine for lipid digestion (2)

A

cholecystokinin (CCK)
- released by intestinal cells (when stomach content enters intestine)
- stimulate bile salt + pancreatic lipase/colipase secretion

secretin
- released by intestinal cells
- stimulate HCO3- release from pancreas→ neutralise acidic chyme from stomach→ provides optimal pH for pancreatic digestive enzymes to work

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10
Q

orlistat function & points to note when consuming

A
  • inhibit release of gastric & pancreatic lipase -> decrease fat absorption
  • take daily supplement of vit A,D,E,K (fat soluble, impaired absorption when lipids are not absorbed into body)
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11
Q

reasons for steatorrhea (excessive fat in feces) & complications

A

impaired lipid digestion
- bile salt deficiency
- pancreatic insufficiency
- disease in small intestine -> affect lipid absorption

complications:
- impaired absorption of vit A,D,E,K

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12
Q

what happens to lipids after absorption into small intestine (3)

A
  1. reforming of initial lipids
    - monoacylglycerol + 2FAs→ TAG
    - cholesterol + FA → CHOLESTEROL ESTER
    - lysophospholipid + FA→ PHOSPHOLIPID
  2. formation of nascent chylomicron
    - TAG, cholesterol esters, phospholipid + fat soluble vitamins→ form nascent chylomicron
    - ApoB-48 (produced by ENTEROCYTES) required for proper assembly of chylomicron
  3. export into lymphatic system
    - chylomicron transport out of enterocyte to lymphatics via EXOCYTOSIS
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13
Q

what is the structure of lipoproteins eg chylomicrons?

A

outer layer
- single layer phospholipid: phosphate group face out; hydrophobic FA chains face inward
- embedded apolipoproteins: essential in structure, metabolism & function of lipoprotein particles

core (lipids)
- TAG, cholesterol esters

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14
Q

where and how do nascent chylomicrons get converted to mature chylomicrons

A
  • movement from lymph nodes (nascent) into blood (mature)
  • HDLs in blood transfer apolipoproteins ApoE and ApoCII to nascent chylomicrons→ mature
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15
Q

what are the apoproteins on mature vs nascent chylomicrons?

A

nascent: ApoB48
mature: ApoCII, ApoE, ApoB48

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16
Q

why do nascent chylomicrons enter lymphatics (and not directly into blood)

A
  • too large to fit through blood vessel (lymphatics have larger gaps between endothelial cells)
  • moves to blood circulation at subclavian vein (not impt)
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17
Q

function of mature chylomicrons

A

converted to energy stores (adipose tissue) or metabolised (muscle):
- ApoCII (LPL co-factor) on mature CM→ activate LIPOPROTEINLIPASE (LPL) on capillary endothelium NEAR MUSCLE tissue/ ADIPOSE tissue→ breakdown of chylomicron core
- LPL converts TAG→ FAs + glycerol
- FA is used to generate ATP in muscle + converted to TG for storage in adipose tissue

uptake by liver for lipogenesis
- glycerol from breakdown of TAG by LPL taken up by liver
- chylomicron remnants contains ApoE -> interact with liver receptor -> uptake via ENDOCYTOSIS -> lysosome in liver fuse with endocytic chylomicron vessels -> degrade chylomicron remnants to from FA, aa, cholesterol, glycerol -> nutrients are taken up by hepatocytes

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18
Q

what are chylomicron remnants

A
  • mature chylomicrons are broken down by LPL -> process cause loss of ApoCII & change in conformation
  • chylomicron remnants no longer have ApoCII, but still contain B48 and ApoE apolipoproteins
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19
Q

hyperchylomicronemia pathogenesis

A
  • genetic, deficiency in LPL/ ApoCII -> impair hydrolysis of TAG in mature chylomicrons
  • severe hypertriglyceridemia
  • xanthoma (lipid buildup under skin) on arms, buttocks, knees due to formation of foam cells in skin (macrophage engulfing lipids)

*patients advised to maintain low fat diet

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20
Q

de novo lipogenesis

A
  • endogenous synthesis of fatty acid from non lipid precursor (usually glucose)
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21
Q

rate limiting step in de novo lipogenesis

A
  • conversion of acetyl CoA to malonyl CoA (catalysed by acetyl CoA carboxylase)
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22
Q

allosteric regulation of ACC (acetyl CoA carboxylase)

A
  • upregulated by citrate
  • inhibited by long chain fatty acyl CoA (-ve feedback)
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23
Q

hormonal regulation of ACC

A
  • upregulated by insulin
  • inactivated by glucagon and epinephrine
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24
Q

where is fatty acid synthase found

A
  • cytoplasm, converts malonyl CoA & acetyl CoA to fatty acid
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25
Q

what is fatty acid synthase expression induced by

A
  • insulin (signals presence of glucose for fat synthesis)
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26
Q

how is TAG (components: FA, glycerol) synthesized in liver

A

FAs
- de novo lipogenesis from glucose

glycerol
- direct glycerol uptake (from chylomicron remnants)
- derive from DHAP (from glucose)

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27
Q

how is TAG synthesized in adipose tissue

A

FAs
- uptake (dietary and hepatic)

glycerol
- derive from DHAP

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28
Q

formation of VLDL process

A
  • lipoprotein synthesized in liver -> secreted from liver as NASCENT VLDL (containing ApoB100)
  • in blood, nascent VLDL acquire ApoE, ApoCII (from HDL) -> forms MATURE VLDL

contents of VLDL
- contains TAG -> FAs are predominantly sythesized by DE NOVO LIPOGENESIS

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29
Q

function of VLDL

A
  • deliver hepatic TAG to other tissue (similar MOA as chylomicrons -> VLDL taken up by muscles & adipose tissue through LPL interaction with ApoCII -> remaining glycerol is taken up by liver)
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30
Q

what happens to VLDL after losing TAG at LPL

A
  • VLDL loses TAG -> becomes smaller sized (intermediate density lipoprotein, IDL)
  • IDL reuptake by liver can occur through interaction with ApoE receptor on IDL
  • IDL can also stay in blood circulation for longer -> lose more TAG -> becomes LDL
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31
Q

steatosis (fatty liver) types (2)

A

accumulation of TAG in vacuoles of hepatocytes
- excessive alcohol intake -> alcoholic fatty liver disease (AFLD)
- metabolic syndrome (eg obesity, diabetes, htn) -> non alcoholic fatty liver disease (NAFLD)

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32
Q

pathogenesis of steatosis in hepatocytes

A
  • increase in FA synthesis by hepatocytes -> cause increase in TAG synthesis
  • rate of TAG synthesis > VLDL synthesis -> accumulation of TAG in liver
  • impaired VLDL secretion
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33
Q

where does fatty acid B-oxidation occur

A
  • mitochondria
34
Q

what does beta oxidation do

A
  • cleaves a long chain fatty acid into many molecules of acetyl-CoA
  • acetyl-CoA enters TCA to produce energy
  • produce FADH2, NADH -> can be used for OXPHOS
35
Q

how is FA transported into mitochondria for beta oxidation

A
  • FA converted to fatty acyl CoA (FACoA) by acyl CoA synthetase -> transported into intermembrane
  • FACoA converted to fatty acylcarnitine by CPT1 -> transported into mitochondrial matrix
  • fatty acylcarnitine converted back to FACoA by CPT2 in mitochondrial matrix -> beta oxidation occurs

*rate limiting step -> carnitine mediated entry (FA-carnitine entry into mitochondrial matrix)

36
Q

regulation of CPT1 in beta oxidation (ie what happens in fed state)

A
  • CPT1 is allosterically inhibited by malonyl CoA
  • high blood glucose (fed state) -> 1) increase insulin release + 2) more glucose converted into citrate -> activate ACC -> increase synthesis of malonyl CoA -> suppress CPT1 -> less FA-carnitine is produced
  • less FA-carnitine in mitochondrial intermembrane -> decrease rate limiting step of carnitine mediated entry -> decrease beta oxidation

*more glucose available -> less beta oxidation to produce glucose

37
Q

what are ketone bodies

A
  • acetoacetate, B-hydroxybutyrate, acetone
  • produced by liver under fasting conditions (ketogenesis)
38
Q

where does ketogenesis occur

A
  • mitochondria of hepatocytes
39
Q

how are ketone bodies produced (under fasting conditions; insulin low glucagon high)

A

adipose tissues:
- glucagon activates HSL (hormone sensitive lipase) -> increase lipolysis -> release FAs

liver
- low insulin high glucagon -> inhibition of ACC (acetyl CoA carboxylase) -> increase beta oxidation (also stimulated by high FA concentration from adipocyte)
- beta oxidation produce acetyl CoA -> converted to ketone bodies in mitochondria

40
Q

HSL vs LPL

A
  • LPL (lipoprotein lipase) cleaves FA from circulating lipoproteins; found on cell membrane of adipocyte
  • HSL (hormone sensitive lipase) cleaves FA from intracellular TAG; found inside adipocyte
41
Q

function of ketone bodies

A
  • exported for use by extrahepatic tissue as fuel (muscles) -> converted back to acetyl CoA in muscle mitochondria -> generate ATP (ketolysis)
  • PROLONG starvation -> used by brain to produce ATP

**conversion of ketone body to acetyl coA requires 3-ketoacyl-coA transferase -> NOT PRESENT in liver -> thus liver DOES not carry out ketolysis

42
Q

how is acetone (lowest amount of ketone body produced) detected

A
  • sweet smell in breath as acetone is volatile
43
Q

how does type 1 DM cause ketoacidosis

A

type 1 DM -> destruction of insulin producing cells in pancreas -> low insulin, high glucagon levels
- high glucagon increase ketogenesis -> rate of ketogenesis > rate of ketolysis -> build up of ketone bodies -> acidosis

*ketonuria present (ketone bodies are soluble in water and excreted in urine)

44
Q

functions of cholesterol

A
  • regulate cell membrane fluidity
  • precursor for synthesis of bile acids, vit D, steroid hormones
45
Q

sources of hepatic cholesterol pool (cholesterol store in liver) (3)

A
  • dietary cholesterol (chylomicron remnants)
  • de novo synthesis in liver
  • cholesterol from extrahepatic tissue (reverse cholesterol transport by HDL
46
Q

how can hepatic cholesterol pool be depleted (3)

A
  • excretion in VLDL (amongst TAG)
  • conversion to bile acid/ salt -> secrete into intestinal lumen
  • small amount of free cholesterol secreted in bile
47
Q

how is hepatic cholesterol store filled by remnant chylomicrons

A
  • mature chylomicrons contain cholesterol & cholesterol esters (cholesterol embedded on outer membrane, cholesterol esters are in core of lipoprotein)
  • after conversion to chylomicron remnants (high cholesterol content as most TAG are lost to LPL) -> ApoE allow remnant chylomicron uptake into liver -> released as cholesterol in liver
48
Q

where does de novo cholesterol synthesis occur

A
  • hepatocytes
  • in cytoplasm and endoplasmic reticulum
49
Q

4 stages of de novo (only need to know stage 1)

A

1) synthesis of mevalonate
2) mevalonate -> activated isoprenes
3) isoprene -> squalene
4) squalene -> steroid

50
Q

what is the rate limiting step in cholesterol synthesis

A
  • conversion of HMG-CoA -> mevalonate (by HMG-CoA reductase)
51
Q

how is HMG-CoA reductase regulated

A

high energy levels
- insulin activate phosphatase -> dephosphorylate & ACTIVATE HMG-CoA reductase

low energy levels
- glucagon, AMP -> activate AMP activated protein kinase -> phosphorylate & INACTIVATE HMG-CoA reductase -> inhibit cholesterol synthesis

52
Q

how is bile acid synthesis (from cholesterol) regulated

A
  • 7a-hydroxylase -> negative feedback inhibition by primary bile acids
53
Q

how are primary bile salts formed from primary bile acids

A
  • conjugation of primary bile acids with TAURINE or GLYCINE
54
Q

why are conjugated bile acids (bile salts) better emulsifiers

A
  • conjugation -> lower pKa -> more molecules have deprotonoted (conjugate base, ie salt) form -> higher solubility -> better emulsifier of lipid
55
Q

bile salt vs bile acid

A
  • non conjugated bile acids -> higher pKa -> majority in HA form -> BILE ACID
  • conjugated bile acid -> lower pKa -> majority in A- (salt) form -> bile salt
56
Q

function of bile salt

A
  • amphipathic molecules -> interact with large lipid droplet -> hydrophobic side faces lipid core, hydrophilic face outside -> breaks down lipid droplet and surround them to form micelles
57
Q

how are secondary bile acids formed

A
  • intestinal bacteria convert primary bile salt to secondary bile acids (deconjugation + dehydroxylation)
58
Q

where are bile salts reabsorbed

A
  • primary bile salts -> reabsorbed at ILEUM via ACTIVE TRANSPORT
  • secondary bile acids -> reabsorbed at COLON via PASSIVE DIFFUSION (less efficient than pri BS reabsorption)

*both pri and sec bile salts are transported to liver via hepatic portal vein

59
Q

how is vitamin D3 obtained by the body

A
  • food
  • endogenous synthesis
60
Q

describe the process of endogenous active Vit D (calcitriol) synthesis in the body

A
  • 7-dehydrocholesterol (immediate precursor of cholesterol) -> converted to Vit D3 (under UV) -> liver converts to 25-(OH)D3 -> transported to kidney
  • at kidney: 25-(OH)D3 binds to Vit D receptor in cytoplasm -> move to nucleus -> complex induce expression of genes -> code proteins to activate 25-(OH)D3 -> form calcitriol (active Vit D3)
61
Q

major lipoproteins

A
  • chylomicrons
  • HDL
  • IDL
  • LDL
  • VLDL
62
Q

how is VLDL converted to IDL

A
  • losing ApoCII and TGs at LPL enzyme -> increase density -> IDL
63
Q

how is IDL converted to LDL

A
  • IDL loses TG to HTGL (hepatic triglyceride lipase)
  • IDL also interacts with HDL to return ApoE receptor

overall LDL has lesser TG + no ApoE (only have ApoB100)

64
Q

fate of LDL in blood

A
  • reabsorbed back into liver via ApoB100 receptor
  • deliver cholesterol/ cholesterol esters to peripheral cells by using its ApoB100 to bind to LDL receptors expressed on peripheral cells
65
Q

what happens to LDL that is neither reabsorbed by liver nor reabsorbed by extra hepatic tissue (due to lack of LDL receptors expressed) during atherosclerosis

A
  • damage to inner wall of artery -> LDL become trapped at damaged side and is OXIDISED -> endothelial cells secrete cytokines when exposed to oxidised LDL -> monocyte accumulation
  • macrophage internalize oxidised LDL -> become foam cells
66
Q

function of HDL

A
  • reverse cholesterol transport (transport cholesterol from extrahepatic tissue to liver)
67
Q

direct reverse cholesterol transport

A
  • HDL synthesized by liver, small intestine -> take cholesterol from extrahepatic tissue cell membranes (converts C to CE and stores it)
  • lipid rich HDL (HDL2) binds to SR-B1 receptor on liver and release C/ CE, TG removed by HTGL
  • lipid poor HDL (HDL3) is released -> continue to pick up more cholesterol from extrahepatic tissue
68
Q

indirect reverse cholesterol transport

A
  • HDL -> exchange CE for TG with VLDL (give VLDL cholesterol), via CETP (cholesterol ester transfer protein)
  • VLDL eventually converted to IDL/ LDL and absorbed (along with cholesterol from HDL)
69
Q

difference between transfer of cholesterol from HDL to liver vs LDL/ IDL to liver

A
  • direct HDL transfer DOES NOT require endocytosis of whole lipoprotein
  • indirect IDL/ LDL transfer require endocytosis of whole lipoprotein
70
Q

familial hypercholesterolemia pathogenesis

A
  • mutation in LDL receptor gene -> ApoB100 cannot induce receptor mediated endocytosis of LDL -> cause ELEVATED LDL particles + elevated LDL-cholesterol in blood
  • homozygous (more severe)/ heterozygous

manifestations
- premature coronary heart disease, AMI, atherosclerosis
- xanthomas present on achilles tendons & hands of pts
- common within family/ relatives if they also have defective gene thus “familial”

71
Q

types of phospholipids (2)

A
  • glycerophospholipid
  • sphingolipid
72
Q

functions of phospholipids

A
  • structural (present on cell membrane, mitochondria membrane, lipoproteins)
  • cellular signaling
73
Q

function of sphingomyelin (specialized form of sphingolipid)

A
  • major structural lipid components of cellular membranes
  • a component of the myelin of neurons -> greatly increase the speed of electrical impulses in neurons
74
Q

how are phospholipids broken down

A
  • phospholipases -> cleave phospholipid into its constituents (FA, glycerol, polar head)
75
Q

examples of eicosanoids

A
  • prostaglandins, thromboxanes, leukotrienes

*ALL are derived from arachidonic acid

76
Q

how is AA production regulated

A
  • by regulation of phospholipase A2
  • phospholipase A2 is activated by diverse stimuli (eg inflammation) -> activation & translocation from cytosol to cell membrane
77
Q

how is arachidonic acid obtained to produce eicosanoids

A
  • present on cell phospholipid bilayer (but exists as a phospholipid)
  • phospholipase A2 cleaves the phosphate head to release arachidonic acid
78
Q

how is arachidonic acid initially synthesized (before attachment to glycerol to form phospholipid and embedded in cell membrane)

A
  • linoleic acid (a type of essential fatty acid)
79
Q

what are essential fatty acids

A
  • omega-3 fatty acid (a-linoleic acid)
  • omega-6 fatty acid (linoleic acid)

**CANNOT be synthesized by body -> must be taken up through diet

80
Q

important products of a-linoleic (ALA) and linoleic (LA) acid

A
  • a-linoleic acid -> synthesize docosahexanoid acid (DHA)
  • linoleic acid -> synthesize arachidonic acid (AA)

*both DHA and AA belong to PUFA (polyunsaturated fatty acids)

Gastro (20 decks)

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