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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #90: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 2

Sep 12, 2017

Lipoprotein metabolism in normal individuals and in type 2 diabetes mellitus

Key points: Triglyceride levels in blood are regulated by the size and number of VLDL secreted from the liver and the efficiency with which triglycerides are cleared from the plasma by lipoprotein lipases. In T2DM, greater numbers of larger, more triglyceride-enriched VLDL are secreted from the liver and lipoprotein lipase activity may be modestly reduced; both lead to increased levels of triglyceride in the blood. HDL cholesterol levels are reduced for several reasons, including increased transfer of that cholesterol to very low- and low-density lipoprotein, in exchange for their triglyceride, by cholesterol ester transfer protein. LDL particles lose some of their cholesterol to VLDL via the same exchange mechanism, which generate smaller, denser, LDL.

Lipoproteins are macromolecular complexes consisting of core lipids, mainly TG and cholesteryl esters (CEs), and surface phospholipids, free cholesterol, and one or more apolipoproteins. Five distinct major classes of lipoproteins have been characterized based on physical characteristics, including separation by ultracentrifugation, molecular weight, diameter, and chemical composition. Lipoprotein subclasses have been further defined based on subtle differences in physical and chemical properties. Notably, in addition to providing structural stability, the surface apolipoproteins impart critical functions to their respective lipoprotein particles [15].

Assembly and secretion of chylomicrons, which are the largest and most TG-enriched lipoprotein particles, occur in the postprandial state, when dietary TGs and CEs must be transferred from enterocytes of the small intestine into the circulation. The assembly and secretion of chylomicrons by the enterocyte is in several ways analogous to VLDL assembly and secretion by the hepatocyte: whereas apo B100 is the necessary, prototypic surface protein associated with VLDL, IDL and LDL, apo B48, a truncated form of apo B100, plays the same role for chylomicrons. Microsomal triglyceride transfer protein (MTP) packages apo B48 with core lipids and is essential to the formation of chylomicrons. Newly assembled chylomicrons, also carrying apolipoproteins A1 and A4, are secreted into the lymphatic system and eventually enter the venous circulation [15]. Studies in animal models of IR and/or diabetes have demonstrated increased intestinal secretion of apo B48-containing lipoproteins, accompanied by increased expression, mass and activity of intestinal MTP [16] and, under certain dietary conditions, an increase in intestinal de novo lipogenesis, likely mediated through activation of a major transcription factor, the sterol response element binding protein 1c (SREBP-1c) [16]. Moreover, studies of men with varying degrees of IR or with T2DM demonstrated increased intestinal production of apo B48-containing TG-rich lipoprotein (TRL) particles [17]. Increased intestinal expression of MTP in people with T2DM may also play a role here. Lewis and Adeli and their colleagues have furthered our knowledge of the assembly and secretion of apo B48-containing lipoproteins, including demonstration of inhibition of chylomicron secretion by acute administration of insulin and glucagon-like peptide 1 [18].The conflicting effects of acute insulin and chronic hyperisulinemia in states of IR suggest that the latter also develops in the intestine.

After entering the plasma, chylomicrons acquire apolipoproteins C1, C2 and C3 (apo C1, apo C2 and apo C3) from the surface of HDL particles. Chylomicron clearance is largely mediated through hydrolysis of core TGs by adipose tissue-derived lipoprotein lipase (LpL) in a process that requires apo C2 as an activator of LpL. In contrast, apo C3 can inhibit LpL-mediated lipolysis. The activity of other factors, including apo A5, which appears to facilitate LpL-mediated lipolysis [19], and angiopoietins 3 and 4 [20,21], which inhibit lipolysis, may also regulate postprandial lipid metabolism. The breakdown of chylomicron TG releases fatty acids (FAs), which are taken up by the local tissue, and produces chylomicron remnant particles. These remnants acquire apolipoprotein E (apo E) from HDL particles and are also enriched in CEs derived from exchange of core lipids with LDL and HDL, the latter process being mediated by cholesteryl ester transfer protein (CETP). Ultimately, chylomicron remnant particles are cleared mainly by hepatic uptake through the interactions of apo E with the hepatic LDL receptor, the LDL receptor-related protein (LRP), and/or cell-surface heparan sulfate proteoglycans. Additionally, hepatic lipase (HL) further hydrolyzes chylomicron remnant particle TG and may augment uptake by the liver. Apo C1 and C3 modulate chylomicron clearance by the liver by interfering in the binding of apo E to its receptors [15].

IR and T2DM affect chylomicron and remnant metabolism negatively at several points in the schema described earlier. For example, there are modest decreases in LpL activity and increases in apo C3 relative to apo C2 levels. Increased apo C3 secretion into plasma has been demonstrated in patients with IR and hypertriglyceridemia [22,23], with impaired LpL-mediated lipolysis of chylomicron TG as well as decreased hepatic uptake of remnant particles the likely results. Recent studies with antisense to apo C3 in hypertriglyceridemia support the important role of this apoprotein in metabolism of TG-rich lipoproteins [24]. Clearance of chylomicrons is competitive with clearance of VLDL and so hepatic overproduction of TG-rich VLDL particles in T2DM can, itself, lead to reduced efficiency of chylomicron clearance [1].This results in increases in circulating TRLs, which are known to be particularly atherogenic [25].

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