Lipoproteins and Apolipoproteins

Lipoproteins

• Have a hydrophobic core of cholesterol ester and triglycerides
• Have a periphery composed of ApoA-I, ApoE, ApoC, ApoA-II, and unesterified cholesterol

Lipoprotein vs Apolipoprotein

• Lipoproteins contain a group of soluble proteins that combine with and transport lipids in blood plasma
  • They act as carrier molecules for hydrophobic lipids
  • They are synthesized in the liver
  • They are composed of a phospholipid and cholesterol outer shell, and a hydrophobic core of cholesterol esters and triglycerides
  • Classes include HDL, LDL, IDL, VLDL, and ULDL
    • LDL increases the risk of coronary heart disease
    • HDL lowers the risk of coronary heart disease
• Apolipoproteins are proteins that bind lipids to form lipoproteins
  • They consist of proteins bound to phospholipids
  • They regulate lipoprotein metabolism and influence normal human vascular biology and the development of atherosclerotic cardiovascular disease
  • They are synthesized in the liver and intestine
  • Classes include apolipoprotein A, B, C, D, E, H, L, and a
    • Apolipoprotein B-100 increases the risk of coronary heart disease
    • Apolipoprotein A-1 lowers the risk of coronary heart disease
      • It regulates HDL metabolism and reverses cholesterol transport
    • Apo B-100, Apo B-48, and Apo a form the structural backbone of atherogenic lipoproteins like VLDL, IDL, LDL, chylomicrons, and lipoprotein a
    • Apo C-II, Apo C-III, and Apo E regulate triglyceride-rich lipoprotein metabolism
• Apolipoproteins serve as structural components in lipoproteins, ligands for surface receptors, and cofactors for enzymes involved in lipid metabolism

Lipoprotein Metabolism - Exogenous Pathway

• Begins in the intestine with the absorption of dietary fats (FFA and cholesterol)
• Chylomicrons lose triglyceride due to lipoprotein lipase, becoming chylomicron remnants
  • These remnants are then taken up by the liver
  • Triglycerides are delivered to peripheral cells
• Some cholesterol is used to synthesize bile

Lipoprotein Metabolism - Endogenous Pathway

• Begins in the liver
• Triglycerides and cholesterol are used to synthesize VLDL
  • Some VLDL lose FFA to peripheral tissue and become IDL
  • IDL may lose some FFA and become LDL
  • LDL is taken up by the liver, which extracts cholesterol from it

Lipoprotein Metabolism - Reverse Cholesterol Transport

• Peripheral cells accumulate cholesterol by taking up circulating lipoproteins
• Cholesterol taken up by HDL is released to the liver
• The level of cholesterol biosynthesis depends on the amount of cholesterol released into the liver by LDL and HDL uptake
• Macrophages' ability to efficiently efflux cholesterol into the reverse cholesterol transport pathway is important in preventing atherosclerosis
  • Transporters like ABCA1, ABCG1, and SR-BI on macrophages break down fat to free cholesterol
    • ABCA1 transports to discoidal HDL
    • ABCG1 and SR-Bi transport to mature HDL
      • Mature HDL can either become cholesterol ester and then VLDL, or directly deliver cholesterol ester to the liver
    • ApoA1 from intestines/liver becomes discoidal HDL and then mature HDL via lecithin cholesterol acyltransferase (LCAT)

Dyslipidemia

• It is a metabolic disorder characterized by elevated LDL-cholesterol levels, which is a major risk factor for cardiovascular disease
  • Can be genetically determined, or secondary to other conditions like diabetes M, obesity, or an unhealthy lifestyle
• LDL cholesterol levels are important in diagnosing familial hypercholesterolemia
• ApoB is diagnostic in mixed dyslipidemia
• Adiposopathy results in increased FFA release, contributing to fatty liver and increased VLDL
• VLDL can become HDL and LDL through metabolic processes involving cholesterol ester-transfer protein (CETP)
  • HDL is more easily metabolized and cleared by the kidneys
  • LDL may be more atherogenic

Drugs for Dyslipidemia

• Atorvastatin (statins)
  • Are HMG-CoA reductase inhibitors
  • Decrease the amount of LDL and TG in the blood
  • Increase the amount of HDL in the blood, but minimally
    • Rosuvastatin may increase HDL levels more effectively
  • Reduce cholesterol synthesis in the liver
    • Less cholesterol synthesis results in more LDL uptake and less VLDL secretion
  • Adverse effects may include myalgia, myostitis/rhabdomyolysis, and transaminitis
• Fenofibrate (fibrates)
  • Are antilipemic agents
  • Are PPAR-ɑ agonists
  • Speed up the natural process of removing cholesterol from the body by reducing cholesterol and TG in the blood
    • They increase the breakdown of TG in VLDL and chylomicrons, which in turn lowers TG levels
    • They decrease VLDL synthesis due to lower TG availability
    • They increase apoA synthesis, which mildly increases HDL
  • Adverse effects include myalgia, rhabdomyolysis, cholelithiasis, and elevations in serum creatinine
• Nicotinic acid/Vitamin B3 (niacin)
  • Raises HDL and lowers LDL by inhibiting VLDL secretion
  • Decreases lipoprotein a
  • Adverse effects may include flushing/vasodilation, impaired insulin sensitivity, gout, and gastritis
• Cholestyramine (bile acid sequestrant)
  • Is a bile acid-binding resin
  • Is strongly positively charged and binds negatively charged bile acids in the intestines, blocking their reabsorption and inhibiting enterohepatic circulation
  • Adverse effects may include increased TG, bloating/constipation, and interference with the absorption of other medications like levothyroxine, warfarin, and digoxin
• Ezetimibe (cholesterol absorption inhibitor)
  • Inhibits NPC1L1 in the intestines to block cholesterol absorption from foods and inhibits the reabsorption of cholesterol ready to be excreted
  • May be used alone or in combination with a statin
  • Lowers LDL and TG
  • Adverse effects include myalgia and rhabdo, though these are very rare