Lipid Metabolism Flashcards by Kyra Porter

phospholipid structure

polar lipids with glycerol backbones and fatty acid tails (can be saturated or unsaturated); amphipathic nature (hydrophobic tails and hydrophilic backbone)

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triglyceride structure

neutral lipids (hydrophobic); this is how we package fat within adipocyte
-one glycerol bound to 3 fatty acids

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lipoproteins

spherical particles required for lipid transport between the tissues; polar lipids & apolipoproteins (activate enzymes) on the surface and hydrophobic tails pointed toward the core

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chylomicron - functions

*delivers dietary TGs to peripheral tissues
*delivers cholesterol to liver in from of chylomicron remnants, which are mostly depleted of their TGs
*generated from dietary fats and secreted by intestinal epithelial cells (made in the small intestine)
*require Apo B48

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what apolipoprotein is on chylomicrons

Apo B48 (also Apo C-II and Apo E)

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lipoprotein lipase - function

*degrades triglycerides in circulating chylomicrons and VLDL
*lipoprotein lipase in the capillaries cleaves the triglycerides in the core of the chylomicrons, releasing free fatty acids and glycerol
*activated by Apo C-II

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LDL (bad cholesterol)

*delivers hepatic cholesterol (from liver) to PERIPHERAL TISSUES
*formed by hepatic lipase modification of IDL in the liver and peripheral tissues
*taken up by target cells via recepor-mediated endocytosis
*if we don’t have enough receptors, it can build up in the blood and cause hyperlipidemia
*apolipoprotein = Apo B100

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apolipoprotein B100

*binds LDL receptor
*only on particles originating from the LIVER (VLDL, IDL, and LDL)

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apolipoprotein E

*medidates remnant uptake: receptor mediated endocytosis of remnants (after chewed up by lipoprotein lipase)
*present on “Everything Except LDL”: chylomicrons, VLDL, IDL, and HDL

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apolipoprotein D

cholesterol ester transfer protein (CETP) of HDL

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apolipoprotein A-1

*found only on alpha-lipoproteins (HDL)
*responsible for ACTIVATION of lecithin:cholesterol acyl transferase (LCAT)

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digestion and uptake of triglycerides into intestinal cells

1) triglycerides (TGs) are partially hydrolyzed by lingual and gastric lipases
2) TGs, some monoglycerides, fatty acids, and other dietary lipids associate with bile salts to form bile salt micelle
3) pancreatic lipase and co-lipase bind to the micelle and complete TG hydrolysis to free fatty acids and monosaccharides
4) micelle docks on intestinal villi; monosaccharides and fatty acids enter enterocyte
5) in enterocyte, monosaccharides and fatty acids put back together into TGs
6) triglycerides and phospholipids packaged into chylomicrons
7) chylomicrons need to acquire Apo B48 to be secreted into lacteals and then into blood

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purpose of carnitine shuttle

bring fatty acids across the inner mitochondrial membrane for beta-oxidation

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steps of carnitine shuttle

1) FFA from acyl-CoA is transferred to carnitine by the enzyme carnitine acyltransferase I (CAT-I) and enters the intermembrane space
2) carnitine-acyl-carnitine translocase brings the acyl-carnitine into the mitochondrial MATRIX
3) CAT-II transfers fatty acid back to CoA to form acyl-CoA in the matrix
4) carnitine shuttled back out to start cycle again; acyl-CoA used for beta oxidation

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fatty acid beta-oxidation

one round of beta-oxidation yields:
1. one acetyl-CoA
2. a fatty acid w/ 2 less carbons on it
3. one FADH2
4. one NADH
*acetyl-CoA enters the TCA cycle
*beta-oxidation keeps going until the entire fatty acid is oxidized

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net yield of ATP from beta-oxidation

106 ATP from a 16-C fatty acid
[108 made, 2 ATP used for activation]

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what is the only organ that can make ketone bodies

the liver (but it cannot use them)

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rate limiting enzyme in formation of ketone bodies

HMG CoA synthase

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rate limiting enzyme in formation of acetyl-CoA from ketone bodies

succinyl-CoA transferase

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which ketone body gets converted to acetyl-CoA

acetoacetate

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ingredients for making complex lipids

backbone, fatty acid, polar head group (to make a phospholipid)

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what is the rate-limiting enzyme for fatty acid synthesis

acetyl-CoA carboxylase (converts acetyl-CoA into malonyl-CoA)

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acetyl-CoA carboxylase

RATE-LIMITING ENZYME OF FATTY ACID SYNTHESIS: converts acetyl-CoA to malonyl-CoA
*requires biotin and ATP to bind CO2
*activated by: citrate & insulin
*upregulates fatty acid synthase gene
*inhibited by glucagon

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fatty acid synthase

*combines 7 malonyl-CoA molecules with 1 acetyl-CoA to form a 16-C fatty acid
*requires 14 NADPH

how does malonyl-CoA regulate fatty acid synthesis and beta-oxidation

-**stimulates fatty acid synthesis** -inhibits carnitine shuttle (to **shut down beta-oxidation**)

triglyceride synthesis in adipocytes

1) insulin promotes GLUT4 transporters on adipocytes, allowing glucose in (as glycerol-3-P) 2) lipoprotein lipase releases free fatty acids from chylomicrons 3) 3 fatty acids are linked to G-3-P to form a triglyceride 4) triglycerides form a globule, which acquires perilipin for storage

triglyceride breakdown in adipocytes

1) **glucagon** binds its receptor, activating adenylyl cyclase, which increases cAMP levels, which activates PKA 2) PKA phosphorylates hormone-sensitive lipase 3) **phosphorylated hormone-sensitive lipase hydrolyzes triglycerides into free fatty acids and glycerol**

hormone sensitive lipase

***degrades triglycerides stored in adipocytes** *promotes gluconeogenesis by releasing glycerol *must be phosphorylated (by PKA) to be active

prostaglandins

functions include vascular permeability, pain, and fever -found in most cells

thromboxanes functions

functions include vasoconstriction and platelet aggregation -found in platelets and macrophages

leukotrienes

functions include **vasoconstriction, vascular permeability, leukocyte attraction, and inflammation** -found in inflammatory cells (neutrophils, macrophages, mast cells)

lipoxins

***terminate the inflammatory response** -found in inflammatory cells (neutrophils, macrophages, mast cells)

what are the inflammatory mediators (eicosanoids)

-prostaglandins -thromboxanes -leukotrienes -lipoxins (resolve inflammation)

where do the inflammatory mediators (eicosanoids) originate from

they all come from **arachidonic acid**

phospholipase A2

*an enzyme that hydrolyzes fatty acids from the 2nd carbon of a phospholipid to **form arachidonic acid** *requires **calcium**

what are the precursors for arachidonic acid

1) linoleic acid (omega 6) 2) linolenic acid (omega 3)

how are eiconasoids made from arachidonic acid

cyclooxygenases (COX 1 and COX 2)

how does aspirin work as a therapeutic drug

aspirin acetylates a serine residue in the active site of COX 1 and COX 2, acting as an **irreversible** inhibitor -this prevents thromboxane synthesis -results in less platelet aggregation and less thrombus formation

what is the rate-limiting enzyme of cholesterol synthesis

**HMG CoA reductase** ## Footnote this is the enzyme inhibited by statins

steps of cholesterol synthesis

acetate -> mevalonate -> activated isoprene -> squalene -> cholesterol

how do statins work

**statins inhibit** (competitive inhibitor) **HMG CoA REDUCTASE**, the rate-limiting enzyme for cholesterol synthesis

receptor basis of familial hypercholesterolemia

LDL receptor mutations (many different types of mutations but most mutations reside in the LDL-binding domain of the receptor)

ATP citrate lyase

converts citrate to acetyl-CoA for fatty acid synthesis

apolipoprotein CII

*cofactor for **lipoprotein lipase** that **catalyzes cleavage** *found on: **chylomicrons, VLDL, IDL, and HDL**

apolipoprotein B48

*mediates **chylomicron SECRETION from enterocyte into lymphatics (lacteals)** *only on particles originating from the intestines (gut): **chylomicrons** and chylomicron remnants

HDL (good cholesterol)

*mediates reverse cholesterol transport **from peripheral tissues to the liver** to be excreted as bile salts or shut down cholesterol biosynthesis *acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism) *secreted from both liver and intestine *alcohol increases synthesis

cholesterol ester transfer protein (CETP)

*mediates **transfer of cholesterol esters to other lipoprotein particles** *activated by apolipoprotein D (on HDL)

hepatic lipase

*degrades triglycerides remaining in IDL and chylomicron remnants

lecithin-cholesterol acyltransferase (LCAT)

*catalyzes esterification of 2/3 plasma cholesterol (ie. required for HDL maturation) *activated by Apo A1

pancreatic lipase

*degrades dietary triglycerides in small intestine

PCSK9

*degrades LDL receptor → increased serum LDL ***inhibition of PCSK9 → increased LDL receptor recycling → decreased serum LDL**

VLDL - functions

*delivers hepatic triglycerides to peripheral tissues *secreted by the liver *apolipoproteins: ApoE, Apo-C2, Apo-B100

IDL - functions

*delivers triglycerides and cholesterol to liver *formed from degradation of VLDL *apolipoproteins: ApoE, Apo-C2, Apo-B100

abetalipoproteinemia - overview

*autosomal recessive *mutation in gene that encodes for **microsomal transfer protein (MTP)** *results in **ABSENT chylomicrons, VLDL, and LDL**

abetalipoproteinemia - clinical presentation

*affected infants present with: -severe fat malabsorption -steatorrhea -failure to thrive *intestinal biopsy shows lipid-laden enterocytes *tx: restriction of long-chain fatty acids, large doses of oral vitamin E

familial dyslipidemias: type I - hyperchylomicronemia

*inheritance: AR *pathogenesis: **lipoprotein lipase or apo C2 deficiency** *increased blood levels of: **chylomicrons, TG, cholesterol** *clinical findings: pancreatitis, hepatosplenomegaly, eruptive / pruritic xanthomas (no increased risk for atherosclerosis) ***creamy layer in supernatant**

familial dyslipidemias: type II - hypercholesterolemia

*inheritance: AD *pathogenesis: **absent or defective LDL receptors or defective apo B100** *increased blood levels of: -IIa: LDL, cholesterol -IIb: LDL, cholesterol, VLDL *clinical findings: high cholesterol, accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, corneal arcus

familial dyslipidemias: type III - dysbetalipoproteinemia

*inheritance: AR *pathogenesis: **ApoE (defective in type thrEE)** *increased blood levels of: chylomicrons, VLDL, TGs *clinical findings: **premature atherosclerosis**, tuberoeruptive and palmar xanthomas

familial dyslipidemias: type IV - hypertriglyceridemia

*inheritance: AD *pathogenesis: **hepatic overproduction of VLDL** *increased blood levels of: VLDL, TG *clinical findings: hypertriglyceridemia (>1000) can cause acute pancreatitis; related to insulin resistance