1. Lipids in the diet are hydrolyzed in the small intestine, and the resultant fatty acids and monoglycerides are repackaged with apoB-48 into TG-enriched chylomicron particles by the intestinal enterocytes and secreted into the lymphatics (1). Dietary chylomicrons bypass the liver and enter the plasma via the thoracic duct, and AHA diets low in saturated fat attenuate their atherogenic metabolic effects. Chylomicrons acquire apoE and apoC-II from HDL, and are hydrolyzed by LPL to smaller TG-depleted, cholesterol-rich chylomicron remnants (2). These apoB-48 and apoE-enriched remnants are taken up by the liver primarily by the LDL receptor-related protein receptor (LDLR) and degraded (3). Endogenous TG is synthesized in the liver from carbohydrate and free fatty acids (FFA) derived from adipocyte hydrolysis by hormone-sensitive lipase (HSL) and adipocyte TG lipase (ATGL), precursors assembled in the Golgi with apoB-100, E, C-II, C-III, and secreted as TG-rich very low-density lipoproteins (VLDL-TG) (4). Obesity-associated hyperinsulinemia stimulates VLDL production, hence, insulin sensitizers and fibric acid derivatives that block VLDL assembly lower insulin-mediated VLDL synthesis and production, and raise LPL to enhance VLDL-TG hydrolysis to apoB-100 and apoE containing VLDL remnants and IDL. These remnant lipoproteins are taken up by scavenger cells or apoE-specific hepatic receptors and degraded in the liver. ApoC-III inhibits LPL-mediated TG hydrolysis and blocks the clearance of apoB-containing lipoproteins from the plasma. The VLDL and IDL remnants are removed irreversibly or hydrolyzed further by LPL and hepatic lipase (HL) to IDL and LDL cholesterol-rich particles (5) to produce apoE, TG-poor LDL particles containing apoB, and CE. The hydrolysis of TG-rich VLDL by LPL also generates free cholesterol and phospholipids (PL), substrates for LCAT. Cholesterol is removed from LDL by the LDLR or oxidized and taken up by CD36 scavenger receptors on macrophages to generate an intracellular free cholesterol pool in the arterial wall (6). Nascent HDL interacts with the ATP-binding cassette transporter-1 (ABCA1) on peripheral lymphocytes to remove excess cholesterol from cells and then binds with apoA-I, the principal activator of LCAT, to esterify cholesterol to form large, spherical cholesterol-ester-rich HDL2 particles (7). Endothelial lipase (EL), a member of the LPL gene family derived from the vascular endothelium, hydrolyzes phosphoglycerol lipids from HDL, reducing HDL size and concentration. Phospholipid transfer protein (PLTP) also transfers phospholipids from lipoproteins to modify the composition of HDL and its conversion into large or smaller particles. Cholesterol is then transported back to the liver directly by HDL or via transfer to apoC-II containing VLDL or IDL by the cholesterol ester transfer protein (CETP). The CETP-mediated interaction of VLDL with HDL exchanges apoCs and apoE from HDL to VLDL, CE from HDL to VLDL and TG from VLDL to HDL. In hyper-TG states a larger pool of TG exchanges with a small pool of HDL- and LDL-CE, resulting in TG-enriched VLDL, LDL, and HDL (8). This lowers the apoA-I content and stability of HDL to reduce HDL levels and change the structure of LDL to a sphere, which impairs binding to the LDLR. Hepatic lipase hydrolyzes TG and PL-enriched HDL, converting HDL2 back to smaller HDL3 particles, reducing the efficient clearance of cholesterol from cells (9).
Source: Dyslipoproteinemia, Hazzard's Geriatric Medicine and Gerontology, 7e
Citation: Halter JB, Ouslander JG, Studenski S, High KP, Asthana S, Supiano MA, Ritchie C. Hazzard's Geriatric Medicine and Gerontology, 7e; 2017 Available at: Accessed: September 22, 2017
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