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Home / Uncategorized / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #91: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 3

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #91: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 3

In the fasting state, hepatic VLDL assembly and secretion predominate. Utilization of nascent apo B100 for the assembly and secretion of VLDL is, to a large extent, limited by substrate availability, namely TG, as apo B100 is constitutively synthesized [26]. In the presence of adequate TG, apo B100 is progressively lipidated through the actions of hepatic MTP, and the newly assembled VLDL particle is transported to the Golgi apparatus, where it may undergo further lipidation before secretion into plasma. The size of the nascent VLDL particles is also determined by TG availability, with a predominance of larger, more buoyant, more TG-enriched VLDL1 and fewer smaller, denser VLDL2 particles produced in the presence of excess hepatocyte TG. Decreased availability of core lipids and/or insufficient MTP activity can lead to both co- and posttranslational degradation of apo B100. Insulin can acutely target apo B100 for post-translational degradation and this may be important in the postprandial period. However, this effect may be significantly diminished in the presence of IR and concomitant chronic hyperinsulinemia and steatosis [27]. Thus, a combination of IR and excess hepatic TG availability results in increased hepatic secretion of both apo B100 and TG even when hyperinsulinemia is present [28–30]. Further complicating this scheme is the ER stress that develops in the presence of IR and fatty liver [31]; apo B100 degradation may be increased by ER stress, leading to less hepatic VLDL secretion and greater steatosis [32]. Thus, a combination of several factors common to IR and T2DM, including hyperinsulinemia, increased FAs, increased lipogenesis, steatosis, ER stress, and apoB degradation, will all play important roles in determining the quantity and size of VLDL secreted from the liver [33].

TG availability is a major driver of VLDL assembly and secretion. FA contribution to the hepatic TG pool is, therefore, a key regulator of that process. Circulating FAs from the peripheral tissues, notably from adipose tissue, FAs derived from chylomicron and VLDL remnant uptake by the liver, and FAs obtained through de novo hepatic lipogenesis are the three sources of hepatic FA for TG synthesis; the major source, by far, being circulating FA [34]. In states of IR and T2DM, all three sources increase hepatic FA [35]. FA flux to the liver is increased as a result of IR in adipocytes, and this can directly stimulate hepatic secretion of apo B-containing lipoproteins [36,37]. Elevated levels of apo B48- and apo B100-containing remnant particles provide TG for hepatic uptake [28]. De novo lipogenesis, the third source of hepatic TG, is likely upregulated via insulin-mediated stimulation of SREBP-1c, a major lipogenic transcription factor. Recent studies indicate that mTOR signaling, both via the mTORC1 and mTORC2 complexes, is central to the “selective” insulin response in the lipogenic pathway in an otherwise insulin-resistant liver [38]. If there is concomitant hyperglycemia, there will also be induction of another transcription factor, carbohydrate responsive element binding protein (ChREBP), which also activates genes required for lipogenesis [30]. Interestingly, the hepatic expression of another nuclear transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), is increased in a number of mouse models of IR and dyslipidemia [39], as well as in humans with hepatic steatosis. In humans, nonalcoholic fatty liver disease (NAFLD), which is closely associated with IR, is characterized by increased hepatic TG derived from de novo lipogenesis [34].

The fate of VLDL particles after secretion initially parallels that of chylomicrons; hydrolysis of VLDL TG by LpL, modulated by the relative proportions of apo C2 and apo C3. Additional regulation of LpL activity derives from the interactions of apo AV, which may facilitate the interaction of TG-rich lipoproteins with LpL at the endothelial cell surface [40] and the angiopoietin-like proteins (angptl3 and angptl4), which interfere with the activity of LpL [41]. Lipolysis of core TG yields smaller, denser VLDL remnants usually referred to as IDL; the efficiency of this process is impaired in the setting of T2DM. Hepatic uptake of VLDL remnants is similar to that of chylomicron remnants, except that VLDL remnants or IDL may undergo further metabolic modifications to generate LDL particles. HL is thought to play an important role in this process. However, despite the increased levels of HL observed with IR and T2DM, conversion of VLDL to LDL is typically reduced. LDL particles are primarily composed of core CEs associated with surface apo B100. As with VLDL remnants and IDL, clearance of LDL occurs mainly through hepatic LDL-receptor-mediated uptake. IR and poorly controlled T2DM can be associated with a reduction in LDL receptors, thereby limiting removal of these particles from the circulation [15,28].

LDL in the circulation can participate in CETP-mediated exchange of its core CE for VLDL or chylomicron TG, resulting in a TG-enriched, CE-depleted LDL particle. Subsequent lipolysis of the TG-enriched LDL particle by LpL or HL produces small, dense LDL. The characteristic hypertriglyceridemia of T2DM is associated, therefore, with the presence of small, dense LDL. It has also been proposed that the large VLDL1 particles that predominate in the setting of T2DM hypertriglyceridemia are avid acceptors of CETP transferred CEs from HDL and preferentially undergo catabolism to give rise to small, dense LDL [15,42]. In addition, the increased HL activity observed in T2DM could play an important role in the production of small, dense LDL particles [15]. The role of small dense LDL has been a longstanding topic of debate, particularly as to whether they are more atherogenic than other apo B-containing lipoproteins [43,44].

 

The “anti-atherogenic” HDL differ considerably in structure and function from the apo B-containing lipoproteins. HDL begins as cholesterol-poor phospholipid discs containing surface apo A1 that is secreted by the liver and intestine. Transfer of intracellular or plasma membrane cholesterol to these nascent particles occurs via the transport protein, ATP-binding cassette transporter A1 (ABCA1). Studies by Parks and colleague demonstrated the critical role of hepatic ABCA1 in the maintenance of plasma HDL cholesterol concentration [45], but transfer of cholesterol from peripheral cells also contributes to HD.This transfer is coupled with cholesterol esterification by the enzyme lecithin:cholesterol acyltransferase (LCAT), accompanied by movement of the product CEs to the core of the maturing HDL3 particle. Apo A1 mediates this process through its ability to activate LCAT. Repeated cycles of this process, together with transfer of cell cholesterol to the maturing HDL particle via ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor B1 (SRB1), give rise to mature, CE-rich HDL2. Mature HDL particles can deliver both free and esterified cholesterol to the liver via interaction with SRB1 [1]. There may be other pathways for HDL uptake by the liver as well.The process just described, at least when the source of free cholesterol is a peripheral cell, has been called reverse cholesterol transport (RCT). It is believed, based on mainly mouse studies, the RCT from cholesterol-laden macrophages in the artery plaque, with eventual hepatic uptake and metabolism, is a critical function of HDL.The fate of apo A1 is less certain, but it is known that significant quantities are taken up and degraded by the kidneys and liver. If CETP-mediated exchange of core lipids is increased, as is the case in the dyslipidemia of T2DM, apo A1 dissociates from the smaller, triglyceride-rich HDL, and clearance of “free” apo A1 by the kidney follows, reducing the plasma apo A1 levels and HDL particle number [15,46].

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