Biochemistry

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Fatty Acid Synthesis

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-FA's synthesized from excess glucose in life & transported to adipose tissue for storage

-FA synthesis in cytosol and requires transport of acetyl-CoA from the mitochondria via the citrate shuttle, carboxylation to malonyl CoA, & linking together of 2 carbons per cycle for form long FA chains. Synthesis stops at C16 palmitoyl-CoA, requiring 7 ATP and 14 NADPH.

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Fatty Acid Metabolism

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-Metabolism takes place by B-oxidation, which takes place in mitochondria, and involves transport of FAs from the cytosol via the carnitine shuttle >> then oxidation removal of 2 carbons per cycle to yield 1 NADH, 1 FADH2, and 1 acetyl-CoA

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Carnitine deficiency

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inability to transport LCFAs into the mitochondria, resulting in toxic accumulation. Causes weakness, hypotonia, and hypoketotic hypoglycemia.

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Acyl-CoA dehydrogenase deficiency

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increased dicarboxylic acids, decrease glucose and ketones. Acetyl-CoA is a positive allosteric regulator of pyruvate carboxylase in gluconeogenesis. decreased acetyl-CoA >> decreased fasting glucose.

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Cholesterol synthesis

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-Rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate.

-2⁄3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT).

-Statins (e.g., lovastatin) competitively and reversibly inhibit HMG-CoA reductase.

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Describe all the lipases and what they do

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-Pancreatic lipase—degradation of dietary triglycerides (TG) in small intestine.
-Lipoprotein lipase (LPL)—degradation of TG circulating in chylomicrons and VLDLs. Found on vascular endothelial surface.
-Hepatic TG lipase (HL)—degradation of TG remaining in IDL.

-Hormone-sensitive lipase—degradation of TG stored in adipocytes.

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What is a chylomicron and what does it do?

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Delivers dietary TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols. Secreted by intestinal epithelial cells.

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Lipoprotein functions

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Lipoproteins are composed of varying proportions of cholesterol, TGs, and phospholipids. LDL and HDL carry most cholesterol.

LDL transports cholesterol from liver to tissues. HDL transports cholesterol from periphery to

liver.

LDL is Lousy. HDL is Healthy.

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Lipid Transport - Chylomicron Metabolism

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Chylomicrons synthesized in enterocytes of SI and enter circulation w/ apoB48 (nascent chylomicron). HDL puts apoCII and apoE on the surface >> mature chylomicron. CPL hydrolyzes TG in the mature chylomicron releasing FAs & glycerol. Chylomicron remnant removed by apoE receptors in the liver.

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Deficiency in apoE?

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-produces type II hyerlipoproteinemia (chylomicron remnants accumulate)

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Lipid Transport - VLDL

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-Nascent VLDL (liver-synthesized TGs), when it enters the circulation from synthesis in the liver, has apoCII and apoE tags placed by HDL

-When CPL activated by apoCII, it hydrolyzes TG in VLDL and as it loses FAs & glycerol, it becomes IDL

Delivers hepatic TGs to peripheral tissue. Secreted by liver.

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Lipid Transport - IDL

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-IDL is either taken up by the liver via apoE receptors, or it continues to be hydrolyzed into LDL

Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.

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Lipid Transport - LDL

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-LDL = primary carrier of cholesterol. IDL >> LDL when apoE lost >> has SINGLE copy of apoB-100

- most tissues have receptors for LDL due to need of cholesterol for cell membrane synthesis or for hormone synthesis (vitamin D, adrenal cortex)

Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.

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Lipid Transport - HDL

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Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine. Alcohol increased synthesis.

CEPT transferse TG to HDL in exchange for CH from HDL >> lower HDL-CH and the amount of CH that can be taken up by the liver and excreted or converted to bile salts/acids.

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VLDL directly affects ______ levels >> ______ risk of CAD

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The higher the VLDL, the lower the HDL-CH level, which increases the risk of coronary artery disease

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What do LCAT and CEPT do?

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-LCAT—catalyzes esterification of cholesterol on HDL
-Cholesterol ester transfer protein (CETP)—mediates transfer of cholesterol esters to other lipoprotein particles (from HDL back to IDL).

- FA added to cholesterol to make CE to keep cholesterol from being transferred to random cell membranes, thus CE kept in center of lipoprotein

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Apolipoprotein E

Function? Seen where?

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-Mediates remnant uptake

-Seen on chylomicrons, chylomicron remanants, VLDL, IDL, HDL

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Apolipoprotein A-I

Function? Seen where?

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-Activates LCAT

-Seen on chylomicron, HDL

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Apoliporpteoin C-II

Function? Seen where?

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-Lipoprotein lipase cofactor/activator

-Seen in chylomicron, VLDL, HDL

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Apolipoprotein B-48

Function? Seen where?

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-mediates chylomicron secretion

-Seen in chylomicron and chylomicron remnant

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Apolipoprotein B-100

Function? Seen where?

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-Binds LDL receptor

-Seen in VLDL, IDL, LDL

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Chylomicron Metabolism summary

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TGs packaged into chylomicron requiring apoB-48 >> nascent chylomicrons enter lymphatics and drain to blood >> nascent chylomicorns obtain apoCII & apoE from HDL >> mature chylomicrons >> TGs hydrolyzed by CPL into FAs and glycerol >> Hydrolysis of chylomicrons by CPL >> chylomicron remnants w/ much less TG (insulin synthesizes CPL in fed state)

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Lipoprotein metabolism summary

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TG synthesized in liver >> w/ help of apoB100, packaged to VLDL & secreted >> TG hydrolysed by CPL into FAs and glycerol >> IDL, which is removed by liver via apoE receptors OR >> IDL loses apoEto become LDL w/ only one apoB100 protein >> LDL removed fromm blood by LDL receptors (apoB100 R) in peripheral tissues

-HDL provides apoE and apoCII to other lipoproteins and removes CH from fatty streaks/plaques via CEPT transferring CH from HDL to VLDL and TG from VLDL to HDL

-IDL & LDL not taken up by liver are taken up by periphery >> macrophages / vessels >> foam cells & fatty streaks

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Type I Familial Dyslipidemia

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-Hyperchylomicronemia

-Increase in chylomicrons, TG, cholesterol

-AR, childhood disease; Lipoprotein lipase deficiency or altered apolipoprotein C-II. Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no increased risk for atherosclerosis).

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Type IIa Familial Dyslipidemia

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-Familial Hypercholesterolemia - polygenic - most common type

-Increase in LDL > 190, cholesterol >260 , TG < 300 mg/dL

-Autosomal dominant. Absent or defective LDL receptors. Heterozygotes (1:500) have cholesterol ≈ 300 mg/dL; homozygotes (very rare) have cholesterol ≈ 700+ mg/dL. Causes accelerated atherosclerosis (premature CAD & may have MI before age 20; early stroke also), tendon (Achilles) xanthomas, xanthelasma and corneal arcus.

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Type IIb Familial Dyslipidemia

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-Familial combined hypercholesterolemia

-AD inheritance; CH and TG begin to increased around puberty. Associated with metabolic syndrome

-Increased in CH and TG >300 mg/dL

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Acquired causes of Type II Dyslipidemia

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-Primary hypothyroidism: decreased synthesis of LDL recetprs

-Blockage of bile flow: bile contains CH

-Nephrotic syndrome: increased liver synthesis of CH

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Type IV Familial Dyslipidemia

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-Hypertriglyceridemia

-increase in VLDL, TG

-Autosomal dominant. Most common hyperlipoproteinemia

-Hepatic overproduction of VLDL. Causes pancreatitis.

-can also have decreased clearnace of VLDL

>> increased risk of CAD and peripheral vascular disease

-See eruptive xanthomas, increase in TG > 300 mg/dL; serum CH normal to moderately increased, LDL < 190, decrease in HDL b/c increase in VLDL

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Acquired causes of Type IV Dyslipidemia

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-Excess alcohol intake: most common cause; increased production of VLDL, decreased activity of CPL

-Oral contraceptives: estrogen increases synthesis of VLDL

-DM: decreased adipose or muscle CPL (decreased VLDL clearance; decreased insulin responsible for decreased synthesis of VLDL and decreased clearance of VLDL)

-Chronic renal failure: increased synthesis of VLDL and decreased clearance of VLDL

---Thiazide diuretics, B blockers: inhibition of CPL >> decreased clearance of VLDL

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Type III Familial Dyslipidemia

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-Familial Dysbetalipoproteinemia or remnant disease

-AR; deficiency of apoE >> decreased liver uptake of IDL and chylomicron remnants

-See Palmar xanthomas in flexor creases

-increased risk for CAD and peripheral vascular disease

-Serum CH and TG > 300 mg/dL. LDL < 190;

-Confirm diagnosis with ultracentrifugation to identify remnants, lipoprotein electrophoresis, identify apoE gene defect