Hepatic Cholesterol Homeostasis

Abstract

T he low-density lipoprotein (LDL) receptor pathway plays a major role in the regulation of the plasma level of LDL in humans. When clearance of LDL particles through the LDL receptor pathway is markedly impaired or abolished, as in familial hypercholesterolemia, 1 profound elevations in plasma LDL result. At the other extreme, more effective clearance of LDL particles by the LDL receptor pathway is the major mechanism by which statins lower plasma LDL. However, these changes in the activity of the LDL receptor pathway are produced by disease or pharmacological intervention and are not evidence of its physiological role.The LDL receptor pathway paradigm stipulates that intracellular cholesterol homeostasis is based on a reciprocal relationship between the rate at which cholesterol within an LDL particle enters the cell through the LDL receptor pathway and the rate at which cholesterol and LDL receptors are synthesized within the cell.2 In brief, cholesterol that enters the cell within an LDL particle is released from the particle in the lysosome and equilibrates with the cholesterol in the endoplasmic reticulum (ER) membrane. The cholesterol mass within the ER membrane determines the activity of the sterol regulatory element-binding protein 2 (SREBP2) pathway, which regulates the synthesis of cholesterol and the LDL receptor.3-5 Additional, more rapid, adaptation mechanisms exist, including esterification of cholesterol by acyl CoA:cholesterol acyltransferase (ACAT) and acute inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCoA reductase, the rate-limiting step of endogenous cholesterol biosynthesis) by hydroxysterols. 6,7 The regulatory paradigm of the LDL receptor pathway is a simple, closed-loop, seesaw homeostatic model: increased uptake is followed by decreased synthesis; decreased synthesis is followed by increased uptake. However, this paradigm was based on studies in cultured fibroblasts, a cell that plays no important role in total body cholesterol homeostasis and a cell with little capacity to secrete cholesterol. In contrast, © 2013 American Heart Association, Inc. Objective-The hypothesis that cholesterol that enters the cell within low-density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles. Approach and Results-We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, ...

PCSK9 and Atherosclerosis - Lipids and Beyond

“…Murine expression of human PCSK9 led to increases in hepatic lipogenesis in both an apoE and LDLR-dependent manner 32) . Moreover, changes in hepatic PCSK9 production correspond to changes in VLDL production 33) . Lastly, PCSK9 deficient mice demonstrate decreased postprandial triglyceride levels 34) .…”

Shunts, channels and lipoprotein endosomal traffic: a new model of cholesterol homeostasis in the hepatocyte

“…ACAT1, expressed at nominal levels and unregulated, is responsible for the cytosolic pool of CE generation stored in the lipid droplets, which is intimately connected to the regulatory pool. ACAT2, which is strongly inducible, produces CE dedicated to VLDL secretion [ 86 ] . The source of cholesterol for ACAT2 is not known, since it is unlikely that ACAT1 and ACAT2 share a substrate pool.…”

“…According to the conventional model of cholesterol homeostasis, LDL-derived cholesterol that is taken up by hepatocytes should enter the regulatory pool, should inactivate SREBP2, and over time, should shut down synthesis of the LDLR as it does in fibroblasts [ 6 ] . However, this does not occur and this suggests that the hepatic LDLR is regulated in a different fashion by cholesterol and other factors [ 86, 88- 99 ] . On the other hand, uptake of CR and the accompanying cholesterol results in a significant downregulation of the LDLR.…”

“…7) LDL-derived cholesterol is a substrate for ACAT2: There is evidence that CR-derived cholesterol is preferentially esterified by ACAT1 through its interaction with the regulatory pool whereas LDL-derived cholesterol is preferentially esterified by ACAT2 [ 86 ] . Importantly, when an ACAT inhibitor is added to LDL-treated cells, the LDL-derived cholesterol does invoke a regulatory effect on LDLR and HMGCR (similar to CR-derived cholesterol) suggesting that esterification of LDL-derived cholesterol is an essential step in its redirection from the regulatory pool.…”

“…Experimental observations have demonstrated this in a primary hamster hepatocyte model but need to be confirmed in other models [ 86 ] . …”