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Biochemistry > Lipid and cholesterol metabolism > Flashcards

Lipid and cholesterol metabolism Flashcards

1
Q

What is the difference between saponifiable and non-saponifiable dietary lipids?

A

Saponifiable lipids have ester group and can react with NaOH to form carboxylic acid salt+alcohol (triglycerides, phosphlipids, sphingolipids)

Non-saponifiable lipids have no ester group, cannot react with NaOH (e..g . derive lipids like eicosanoids, bile salts, sterols, Vit D)

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2
Q

Are lipids hydrophobic or hydrophilic?

A

Hydrophobic, needs micellar structures for their transportation in aqueous medium

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3
Q

What is the main component of dietary lipids?

A

Triglycerides make up 90% of dietary lipids,

remaining include cholesterol, cholesterol ester, fatty acids, phospholipids

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4
Q

How are triglycerides stored?

A

In anhydrous form in adipose tissue

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5
Q

How are triglycerides transported?

A

in lipoprotein particles in blood

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6
Q

What is saturated fat?

A

no double bond

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7
Q

What is unsaturated fat?

A

1 or more double bond

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8
Q

What is the relation between the number of double bonds and the melting temperature of lipids?

A

The more the double bonds, the lower melting temperature of the lipids.

When there are more double bonds, there are more kinks in the structure and thus FA does not pack well together

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9
Q

The more unsaturated the FAs in the phospholipid membrane, the _____________ the membrane fluidity?

A

greater

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10
Q

Why do more unsaturated fatty acids become rancid faster?

A

The double bonds can be cleaved by free-radical reactions involving molecular oxygen, and highly volatile aldehydes and ketones will be released

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11
Q

What are trans fats?

A

Trans C=C bonds are introduced by partial hydrogenation of cis-unsaturated fats. Removes most double bonds, reforms some and alters FA shape.

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12
Q

What are omega 3 and omega 6 fatty acids used for?

A

Synthesis of eicosanoids (prostaglandins, thromboxanes and leukotrienes)

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13
Q

How do trans C=C bonds in omega 3 and omega 6 fatty acids affect formation of eicosanoids?

A

Cyclooxygenase and lipooxygenase are less effective on FAs with trans C=C bonds.

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14
Q

What are the other negative side effects of transfats?

A

High amount of transfat in fiet, incorporation in PL membranes, lowered membrane fluidity as transfats pack more effectively. Abnormal cellular function and higher risk of coronary heart disease and atherosclerosis

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15
Q

What are the two sources of lipids in our body?

A

Diet, and de novo synthesis from acetyl-CoA

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16
Q

What does hydrolysis of triglyceride yield?

A

Fatty acids and glycerol

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17
Q

Why can’t triglycerides form micelles or bilayers like phospholipids?

A

Triglycerides have no polar groups and form aggregates in adipocytes

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18
Q

Where does digestion of triglycerides occur mainly?

A

In the duodenum

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19
Q

What is TG digested by?

A

Lipase

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20
Q

What are the different types of lipase?

A 
Lingual lipase (salivary gland)
Gastric lipase (stomach)
Pancreatic lipase (main enzyme)
Colipase (binds to dietary TG and pancreatic lipase simultaneously to allow active site of lipase to access TG)
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21
Q

Describe the break down of TG

A

TG—Pancreatic lipase—> 2-mono-acylglycerol + 2 FFAs

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22
Q

How are cholesterol esters digested?

A

CE—Pancreatic cholesterol esterase—> FFA+ cholesterol

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23
Q

How is membrane phospholipid digested?

A

Membrane PL—Phospholipid A2—> FFA +Lysophospholipid

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24
Q

What is the function of bile salts in digestion of dietary lipids?

A

Bile salts emulsify fats into small droplets to increase the surface area. Lipid digestion occurs at lipid-water surface.

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25
Q

What is the fate of bile salts after dietary lipids have been digested?

A

Bile salts are left behind in the intestinal lumen and are mostly actively reabsorbed in the terminal ileum

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26
Q

What triggers the release of bile acids?

A

Cholecystokinin is released when food enters the small intestine and it signals the gallbladder to release bile acids and the pancreas to release digestive enzymes.

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27
Q

What does secretin do?

A

It stimulates cells in the duodenum to release bicarbonate to increase the pH to approx pH 6 which is the optimal pH for digestive enzymes in the intestine

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28
Q

What is the meaning of amphipathic?

A

When a molecule has both hydrophilic and hydrophobic parts, it is amphipathic

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29
Q

Which molecules are amphipathic?

A

Bile salts and phospholipids

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30
Q

What is a mixed micelle?

A

Bile salts= 2-MG+FA+Cholesterol+PL+Fat soluble vitamins

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31
Q

What does a mixed micelle do?

A

It is brought to enterocytes to allow lipid-soluble components in the micelle to diffuse into the enterocyte

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32
Q

What happens to 2-MG and FA in the enterocytes?

A

TG is reformed by FA-CoA

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33
Q

What happens to the absorbed cholesterol in the enterocytes?

A

Cholesterol converted to cholesterol esterase by acyl-CoA cholesterol acyltransferase (ACAT)

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34
Q

What is a nascent chylomicron?

A

TG (rich)+ cholesterol+ cholesterol ester+ fat soluble vitamins assembled as lipoprotein micellar structure with phospholipids forming the shell. ApoB-48 synthesised by enterocytes inserted into shell at ER.

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35
Q

how are nascent chylomicrons transported to blood?

A

As nascent CM are too large to enter endothelial cells, they are secreted by intestinal epithelial cells into lacteal (lymphatic capillary) of lymphatic system. It is transported to the blood via thoracic duct

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36
Q

Which apolipoproteins do nascent CM gain from HDL?

A

Nascent CM gains ApoC-II and ApoE from HDL to form mature CM

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37
Q

What is the function of ApoC-II?

A

ApoC-II activated Lipoproteinlipase at the endothelial cells of capillary

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38
Q

What does lipoproteinlipase do?

A

Breaks down TG in CM to release FA and glycerol

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39
Q

What is the fate of FA after being produced in mature CM?

A

Either enter muscle for energy production or adipocytes for storage

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40
Q

What is the fate of glycerol after being produced in mature CM?

A

Metabolised in the liver for TG synthesis in fed state

Metabolised in liver for gluconeogenesis in fasted state

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41
Q

What happens to ApoC-II after the breakdown of TG in the mature CM?

A

it is returned to HDL

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42
Q

What is a mature CM called after the TGs are degraded and most of TG is lost?

A

It becomes a chylomicron remnant.

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43
Q

What does ApoE do on the surface of a chylomicron remnant?

A

ApoE is recognised by ApoE receptors on hepatocytes. CR endocytosed into hepatocytes and broken down completely by lysosomal enzymes.

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44
Q

What is produced by the breakdown of chylomicron remnants?

A

Fatty acids, glycerol (recycled into TGs and transported in blood to peripheral tissues as VLDLs), amino acids, PO4, Cholesterol

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45
Q

How does a fat blocker (Orlistat) work?

A

Inhibits pancreatic lipase, and thus TG digestion into 2-MG and FFA.

This results in TG excreted in faeces (steatorrhea: excretion of abnormal amount of fat in faeces), lower absorption of lipids

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46
Q

What is hyperchylomicronemia (type I hyperlipidemia) caused by?

A

Genetic defect in LPL or ApoC-II, TG in mature chylomicron not broken down

High CM levels, high TG levels

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47
Q

What are the effects of hyperchylomicronemia?

A

Large particles may obstruct capillaries, local ischaemia, restricted blood flow.

Eruptive xanthomas on arms, buttocks and knees (accumulation of TGs in phagocytic cells

Pancreatitis: Cellular damage exposes TG to pancreatic lipase, breakdown TG and release FFA, cytotoxicity of FFA exacerbate injury, leading to an increase in inflammatory mediators and free radicals

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48
Q

How can you treat hyperchylomicronemia

A

Maintain low fat diet to alleviate symptoms.

Orlistat to excrete TG in faeces

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49
Q

What could lipid malabsorption (steatorrhea) be caused by

A

Lack of bile acids due to liver damage (no emulsification of fat droplets

Defective secretion of pancreatic juices (TGs not broke down to enter enterocytes)

Defective mucosal cells (cover surface of duodenum, lipids cannot be absorbed)

Short bowel syndrome (prevent complete digestion of lipids)

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50
Q

What is the effect of lipid malabsorption?

A

Reduce micelle formation which aids in transport to enterocytes, reduced absorption of LCFA, cholesterol and fat soluble vitamins

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51
Q

How can lipid malabsorption be treated?

A

Administration of SCFA and MCFA oral supplements which are least hydrophobic and can be absorbed directly into enterocytes without forming micelle.

Oral supplements of pancreatic enzymes or bile salts according to deficiency

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52
Q

What are the long-term effects of a fat-free diet?

A

Insufficient fats to form mixed micelles, Fat-soluble vitamins and essential FA cannot diffuse into enterocytes, lower/no intake.

Enterocytes cannot form chylomicrons to transport essential FA and FSV

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53
Q

What are the 2 sources of NADPH

A

PPP and malic enzyme reaction (malate-> pyruvate)

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54
Q

Describe how citrate produced in the TCA forms pyruvate and NADPH

A

Citrate in the mitochondria leaves into the cytosol via transporter. In the cytosol, citrate breaks down into acetyl CoA and OAA. OAA is converted to malate, using 1 NADH and giving 1 NAD+

Malate is converted to pyruvate by malic enzyme, producing NADPH

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55
Q

What can inhibit the citrate transporter?

A

LCFA (end-product of FA synthesis)

Product inhibition, where LCFA inhibits production of NADPH, and thus inhibits FA synthesis

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56
Q

What is the committed step in FA synthesis?

A

Acetyl-CoA converted to malonyl-CoA by acetyl-CoA carboxylase (ACC)

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57
Q

What does the conversion of acetyl-CoA to malonyl-CoA require and produce?

A

CO2 and biotin required

ATP used, producing ADP and Pi

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58
Q

How is the committed step in FA synthesis regulated?

A

Positive regulation by citrate and dephosphorylation of ACC (insulin)

Negative regulation by LCFA-CoA and phosphorylation of ACC (glucagon and epinephrine)

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59
Q

How does citrate activate ACC?

A

It facilitates formation of active ACC filaments via polymerisation so that ACC becomes an active polymer

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60
Q

How does LCFA-CoA (e.g. palmitoyl-CoA) inhibit ACC?

A

It causes ACC filaments to disassemble into inactive ACC dimers

61
Q

How do hormones affect ACC acitivity?

A

Insulin activates protein phosphatase to dephosphorylate ACC and activate it.

Glucagon and epinephrine activates AMP dependent kinase to phosphorylate ACC and deactivate it

62
Q

How is amount of ACC regulated by diet?

A

Prolonged consumption of high calorie, high carb diets increase synthesis of ACC enzyme

Prolonged fasting or caloric restriction can reduce the synthesis of ACC enzyme

63
Q

What is fatty acid synthase (FAS)?

A

It is a multienzyme complex containing an acyl carrier protein (ACP) that can bind to malonyl CoA. FAS elongates the acyl chain stepwise by adding 2-C from malonyl CoA each time until palmitoyl CoA is formed

64
Q

When does elongation end?

A

When palmitate is released from FAS via hydrolysis

65
Q

What electron carrier does fatty acid synthesis require?

A

NADPH

66
Q

Where does chain modification take place?

A

In the endoplasmic reticulum

67
Q

What are the different kinds of chain modification?

A

Chain termination, chain elongation and desaturation

68
Q

How are MCFAs synthesised?

A

They are synthesised in the mammary gland.

Thioesterases cleave the shorter chains from FA synthase complex. (chain termination)

69
Q

How does chain desaturation occur?

A

Fatty acyl-CoA desaturases convert saturated fatty acyl-CoA to an unsaturated one.

Desaturases in humans and animals can only introduce double bonds from omega 9 onwards.

FA with double bonds in omega 1 to 8 positions are obtained from diet.

70
Q

Why are MCFAs synthesised in the mammary glands?

A

Intestinal immaturity in infants, so MCFA in breast milk will allow it to be absorbed directly

71
Q

How is newly synthesised FA converted to TG in the liver?

A

2 fatty acyl-CoA is added to glycerol-3-phosphate to form phosphatidic acid, add 1 fatty acyl-CoA, forms TG

72
Q

What other molecules can be generated by phosphatidic acid?

A

Phospholipids.

73
Q

How is glycerol-3-P generated?

A

In liver, glycerol converted to G3P by glycerol kinase

In liver, glucose converted to DHAP in glycolysis, then G3P.

In adipose, pyruvate converted to DHAP then G3P via glyceroneogenesis in fasted state

74
Q

What are the similarities in VLDL and chylomicrons?

A

both are micellar structures

Both carry a lot of TG, some phospholipids, some cholesterols and some cholesterol esters

Both are synthesised as nascent particles, becoming mature via obtaining ApoC-II and ApoE from HDL

75
Q

What are the difference in CM and VLDL?

A

CM has ApoB-48, VLDL has ApoB-100

CM is synthesised by enterocytes, VLDL synthesised by hepatocytes

CM transports absorbed TG (exogenous) to muscles, adipocytes, liver
VLDL transports de novo synthesised TG (endogenous) to adipocytes

76
Q

What is a nascent VLDL?

A

TG rich, cholesterol, cholesterol ester, phospholipids, proteins, ApoB-100

77
Q

What secretes nascent VLDLs?

A

Hepatocytes

78
Q

What does a nascent VLDL gain from HDL to become a mature VLDL

A

ApoC-II and ApoE

79
Q

What does ApoC-II activate at the endothelial cells of capillary?

A

It activates LPL to break down TG in VLDL to release FA and glycerol

80
Q

Where do FAs go after being released?

A

Enter muscle for energy production OR

enter adipocytes for storage.

81
Q

Where does glycerol go after being released from VLDL?

A

To the liver,
For gluconeogenesis in fasting state
For TG synthesis in fed state

82
Q

What is an IDL?

A

When VLDL loses most of TG.

IDL has ApoE on surface

83
Q

What does ApoE in IDL do?

A

ApoE receptors on hepatocytes recognise ApoE and some IDL is endocytosed into hepatocytes.

TG broken down by ApoE-dependent hepatic lipase, more TG lost, thus LDL is formed. (C, CE>TG)

84
Q

What happens to ApoC-II and ApoE after LDL is formed?

A

They are returned to HDL

85
Q

Which apolipoprotein does LDL have?

A

ApoB-100

86
Q

What is the function of ApoB-100

A

it is recognised by LDL receptors on hepatocytes. Some (60%) of LDL endocytosed into hepatocytes

87
Q

What happens to remaining LDL (40%)

A

Taken up by extra-hepatic tissue via same LDL receptor mechanism. Adrenal cortex and gonads, cholesterol used for steroid hormone synthesis and maintaining fluidity of cell membrane

88
Q

What is fatty liver (steatosis)?

A

Accumulation of TG in hepatocytes, reversible

89
Q

What is the biochemical basis of alcoholic fatty liver?

A

Ethanol—alcohol dehydrogenase(ADH)—> acetaldehyde (toxic)—aldehyde dehydrogenase (ALDH)—>acetate

NAD+ consumed and NADH produced.

When alcohol is consumed, high NADH levels in liver. High NADH/NAD+ ratio, inhibits the TCA cycle, acetyl-CoA accumulates in liver, increased malonyl CoA synthesis by ACC. High malonyl-CoA inhibits Carinitinepalmitoyltransferase I (CPT I). FA in cytosol not transported into mitochondria, so no beta oxidation of FA, FA accumulates in liver .

G3P synthesis increases from NADH converting DHAP to G3P.

G3P+FA in liver results in TG synthesis.

Acetaldehyde is cytotoxic, inhibits tubulin polymerisation, and inhibits VLDL secretion. Therefore, TG retained in liver

90
Q

How do you treat alcoholic fatty liver?

A

Reduce alcohol consumption

Antabuse (sidulfiram) inhibits aldehyde dehydrogenase (ALDH)

Acayeldehyde (cytotoxic) build up, stimulate flushing, nausea, palpitations, prevent consumption of more alcohol

Increase in AST, AST:ALT>2

91
Q

What is the biochemical basis of non-alcoholic fatty liver?

A

Due to insulin resistance (Type 2)
Insulin receptors on hepatocytes become less responsive to insulin, liver increases TG storage, fall in FA oxidation, increase in FA synthesis and uptake, fall in secretion of FA into blood as lipoproteins. Thus, accumulation of FA.

Increase in ALT, sometimes AST

Due to insulin deficiency (Type 1), HSLs continue being activated, break down TG to glycerol and FFAs. FFAs not used for energy, circulate back to liver due to increased uptake. Less secretion of FA into bloodstream and less FA oxidation. Liver reassembles TG at higher rate due to insulin resistance. Enzyme in liver that secretes VLDL breaks, accumulation, fatty liver

92
Q

What is abetalipoproteinemia?

A

ApoB-48 and ApoB-100 deficiency.
Synthesis and secretion of CM and VLDL impaired. Inability to absorb dietary fats, cholesterol and fat soluble vitamins, accumulate in enterocytes and hepatocytes.

FSV (Vit A, D, E, K) deficiency

Lipid accumulation

93
Q

How does persistent overconsumption od carbs cause obesity despite moderate fat intake

A

Glucose converted into acetyl CoA, in excess of energy requirements, converted to TG+C in liver. Packaged as VLDL and secreted into blood, VLDL broken down by LPL at target tissues.

FA converted to TG for storage in adipose tissue and to triglycerides in muscle.

94
Q

What does long-term high insulin:glucagon ratio lead to?

A

high ACC and FAS synthesis, increased FA synthesis and lipogenesis

High G6PD synthesis in PPP, increased NADPH for FA synthesis

Increased LPL synthesis, increased TG broken down at adipocytes, increased FA entering adipocytes for storage

95
Q

What is the hormonal trigger for the release of FAs from TG stores in the adipose during starvation?

A

Low insulin:glucagon ratio

96
Q

What is the key lipolytic enzyme in adipose tissue?

A

Hormone sensitive lipase (HSL)

97
Q

How does low insulin:glucose ratio lead to lipolysis?

A

Adenylyl cyclase activated, increased cAMP, activates protein kinase A to phosphorylate HSL, HSL activated to break down TG into FA (mainly LCFA) +glycerol

98
Q

What is the fate of glycerol produced in lipolysis?

A

Converted into glyceraldehyde-3P, produces glucose via gluconeogenesis since insulin:glucagon ratio low

99
Q

What is the fate of FA produced in lipolysis?

A

Transported in blood bound to serum albumin to tissues that require energy. Oxidised to produce acetyl-CoA which enters TCA cycle to produce ATP

100
Q

What transports FA across plasma membrane into cytosol?

A

FA-binding proteins.

101
Q

What happens to FA in the cytosol?

A

FA is activated into fatty acyl-CoA by CoA-SH.

102
Q

How does fatty acyl-CoA pass through the mitochondrial membrane?

A

Fatty acyl-CoA binds with carnitine, catalysed by carnitine palmitoyl transferase (CPT I) found on mitochondrial membrane, producing fatty acyl-carnitine, which is brought across inner mitochondrial membrane by translocase. Inside mitochondrial matrix,CPT II catalyses release of fatty acyl-CoA and carnitine.

103
Q

What happens to carnitine after being released by CPT II inside mitochondrial matrix?

A

It is transported out by translocase to continue to transport fatty acyl-CoA across

104
Q

What happens to fatty acyl CoA after beig transported into the mitochondrial matrix?

A

Undergoes betaoxidation

105
Q

What is an inhibitor of CPT-I?

A

malonyl-CoA, produced during FA synthesis.

Fatty acyl-CoA cannot enter mitochondria and FA oxidation is prohibited

106
Q

Do MCFA and SCFA require carnitine to be transported into mitochondria?

A

No. Thus, entry of MCFA and SCFA into the mitochondria is not inhibited by malonyl-CoA

107
Q

How many Cs are removed from the Fa-CoA chain during each beta oxidation spiral?

A

Each beta oxidation spiral shortens fatty acyl-CoA chian by 2-C, liberating acetyl CoA which is oxidised in the TCA cycle to produce ATP

108
Q

Aside from acetyl CoA, what does beta oxidation produce that contributes energy?

A

FADH2 in first step and NADH in third step, converted to ATP in the ETC

109
Q

What are the 4 steps of beta oxidation?

A

oxidation, hydration, oxidation and cleavage

110
Q

What does beta oxidation of odd-chain FA yield?

A

Propionyl-CoA (3C) which can be converted to succinyl-CoA which enters TCA cycle to produce OAA, which can be used for gluconeogenesis.

111
Q

Why do unsaturated FAs require accessory enzymes for beta oxidation to proceed?

A

50% of FA in the diet contains cis double bonds. Location of cis bonds can prevent the formation of trans-deltasquared bond. Accessory enzymes required to convert cis double bonds to trans delta squared bond for beta oxidation to proceed

112
Q

What is the extra step required for the complete oxidation of VLCFA?

A

oxidation that takes place in peroxisomes.

Beta oxidation of VLCFA, shortened to MCFAs and SCFAs.

Transferred to mitochondria for complete beta oxidation.

113
Q

What is the enzyme in peroxisomal oxidation of VLCFA?

A

Acyl CoA oxidase, not coupled to ATP synthesis.

Produces H2O2 which is converted to H2O+O2 by catalase.

Both enzymes are only found in peroxisome and only involved in VLCFA oxidation.

114
Q

What other oxidation occurs in peroxisome.

A

alpha oxidation of branched-chain FAs (from plants) and methylated phytanic acid (from dairy products)

115
Q

How else are FAs oxidised?

A

omega oxidation of FAs producing dicarboxylic acids (minor pathway)

116
Q

When does omega oxidation become a significant pathway?

A

When mitochondrial beta oxidation is defective. It is an effective mechanism for eliminating toxic levels of FFAs. Dicarboxylic acids produced are shortened by betaoxidation to succinate and adipate which are excreted in urine.

117
Q

What is MCADD?

A

Medium-chain acyl-CoA dehydrogenase deficiency occurs as a result of beta oxidation of MCFAs in mitochondria being blocked. Increased urinary excretion of dicarboxylic acids and medium-chain acyl-carnitines.

Susceptible to severe hypoglycemia because tissues are reliant on glucose. Fasting should be avoided.

118
Q

How do FA oxidation disorders usually present?

A

Hypoketosis: FA oxidation decrease, decrease in acetyl-CoA and no excess acetyl-CoA for ketogenesis

Hypoglycemia: increase in reliance on glucose for energy

119
Q

What is the hormone stimulus that results in ketogenesis?

A

Prolonged fasting, low insulin:glucagon ratio, adipose release FA via lipolysis, inhibit ACC, drop in malonyl-CoA production, CPT-I not inhibited, fatty acyl-CoA enters mitochondria for beta oxidation, generates high levels of NADH and ATP (from acetyl-CoA)

Inhibits isocitrate d/h produces NADH, less malate produced from isocitrate, OAA-malate equilibrium shifts to malate.

Proteolysis encouraged, glucogenic amino acids produced, converted to OAA then malate.

Malate exits mitochondria and converted to pyruvate by malic enzyme, participates in gluconeogenesis (triggered by high NADH/NAD+ ratio) in cytosol

Low OAA levels left in mitochondria limits TCA cycle, and acetyl-CoA accumulates. After ATP requirement is met, excess used for ketogenesis.

During starvation, ketogenic amino acids broken down during starvation to produce KB and contribute to ketogenesis.

120
Q

What does the brain use for fuel?

A

KBs and glucose. Cannot use FFA

121
Q

Describe the process of ketogenesis

A

2 acetyl-CoA—thiolase—> CoASH+acetoacetyl CoA

AcetoacetylCoA—HMG CoA synthase—>HMG CoA (AcetylCoA—>CoASH)

HMGCoA—HMG CoA lyase—>Acetoacetate+acetyl CoA—>betahydroxybutyrate or acetone

122
Q

What is the difference between mitochondrial HMG CoA synthase and cytosolic HMG CoA synthase?

A

Mitochondrial CoA synthase involved in ketogenesis.

Cytosolic HMG CoA synthase involved in cholesterol synthesis

123
Q

How does type I diabetes result in ketonemia, ketouria and ketoacidosis

A

Ketogenesis exceeds ketolysis, high KB in blood leads to acidemia. Excretion of glucose and KBs in the urine leads to dehydration, increases [H+] in the plasma (ketoacidosis)

124
Q

What are the 3 kinds of KB produced in the body?

A

Acetone
Acetoacetate (spontaneously decomposed to acetone, enzymatically reduced to betahydroxybuyrate)
Beta-hydroxybutarate

125
Q

Are KBs water soluble?

A

Yes, can be transported in blood without carrier

126
Q

What are the three steps of ketolysis of beta-hydroxybutyrate?

A

Oxidation, activation and cleavage

Gives 2 acetyl CoA and 20 ATPs

127
Q

What is the benefit of ketogenesis and ketolysis?

A

Glucose synthesised via gluconeogenesis spared and reliance on proteolysis is also reduced

128
Q

How is lipogenesis regulated in the short term when well fed (high insulin:glucagon ratio)?

A

Activate ACC in liver: FA synthesis

Activate FAS in liver: lipogenesis

Activate GLUT4 transporter at adipocytes: increase glucose uptake into adipocytes, converted to G3P for TG synthesis

Increase LPL secretion at adipocytes: breakdown CM and VLDL to form FA which enter adipocytes, combine with G3P to form TG

Inhibit HSL in adipocytes, inhibit TG breakdown

129
Q

How is lipogenesis regulated in the long term when well fed (high insulin:glucagon ratio)?

A 
Increase in amount of enzymes
Increase ACC
Increase FAS
Increase LPL secretion at adipocytes
Increase malic enzymes and G6PD synthesis to generate more NADPH for FA synthesis
130
Q

How is lipolysis regulated in the short term when fasting (low insulin:glucagon, epinephrine ratio)?

A

Activste adenylyl cyclase, increase cAMP, activate PKA, activate HSL via phosphorylation, stimulate lipolysis, glycerol and FA produced

Inhibit ACC via phosphorylation of AMP-dependent kinase, inhibit lipogenisis

increase glycerol used for gluconeogenesis in liver

Increase FA oxidised by tissues for energy and also converted to KB in liver

Increase in KB oxidised by brain for energy

FA released by HSL exceeds required for energy produciton, remaining FA (40%) in adipocytes reesterified with G3P into TG, G3P generated from gluconeogenic substrates. TG synthesis occurs during fasting.

131
Q

How is lipolysis regulated in the long term when fasting (low insulin:glucagon, epinephrine ratio)?

A

Fall in amount of enzymes involved in FA synthesis (ACC, FAS, LPL)

Cortisol released, increased lipolysis at adipocytes
Proteolysis occurs, release ketogenic and glucogenic amino acids from proteins for ketogenesis and gluconeogenesis respectively

132
Q

Describe the effect of cortisol during acute stress

A

Stimulates gluconeogenesis in liver, increase glucose for fight or flight

Activates protein kinase A, activates HSL via phosphorylation, lipolysis and proteolysis, produce FA and amino acids for gluconeogenesis

Appetite suppressed

133
Q

Describe the effect of cortisol during chronic stress (Cushing)

A

Increased appetite, highr insulin, LPL activated, lipogenesis

Acetyl CoA from glucose in excess of energy requirements, FA synthesis

Adipocytes in abdomen have more stress hormone receptors, more sensitive to insulin. More fat deposited around abdomen

134
Q

How does stress lead to cytotoxic levels of LCFA in plasma

A

Lipolysis releases LCFA and glycerol to provide energy for fight or flight, but most modern day stress mostly psychological, LCFA not required

135
Q

How does type 2 diabetes mellitus lead to high plasma levels of unesterified LCFA

A

Insulin resistance, HSL not inhibited, TG broken down in adipocytes, FFA transported to liver, increase in TG synthesis, increase in VLDL, broken down by LPL at adipocytes, increase in FFA at adipocytes, increase in TG formation, broken down by HSL, vicious cycle

136
Q

What is phosphatidic acid?

A

2 fatty acyl-coA groups added to G3P

137
Q

How do you form phospholipids from phosphatidic acid?

A

Add polar head groups to phosphate of phosphatidic acid

138
Q

What is Neimann Pick Disease?

A

Defective sphingomyelinase. Sphingomyeline not degraded into ceramide+phosphoryl-choline. Accumulation in monocyte-macrophage system and CNS.

139
Q

How are prostaglandins and thromboxanes formed?

A

Via cyclo-oxygenase activity on arachidonic acid.

140
Q

How are leukotrienes formed?

A

Lipoxygenase activty with arachidonic acid

141
Q

How are epoxyeicosatrienoic acid (EET) formed?

A

CYP450 on arachidonic acid

142
Q

What is arachidonic acid?

A

Released from PL by phospholipase A2

Polyunsaturated C-20 FA found in membrane PL

omega 6 FA derived from linoleic acid

143
Q

What do non-steroidal anti-inflammatory Drugs (NSAIDs) do?

A

Inhibit COX 1 and 2

144
Q

What does aspirin do?

A

Inhibit Cox 1

145
Q

What is the difference between COX-1 and COX-2?

A

COX-1 is constitutive and serves homeostatic functions, inhibition undesirable

COX-2 is induced, and causes inflammation, inhibition desirable

146
Q

What does ApoA-1 do?

A

Activated LCAT

147
Q

Where is Apo-A1 found?

A

HDL

148
Q

What does LCAT do?

A

It converts cholesterol from peripheral tissue to cholesterol esters immediately after HDL takes in cholesterol, and maintains cholesterol gradient so that HDL can continue to uptake cholesterol

Biochemistry (3 decks)

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