Regulates hepatic cholesterol biosynthesis.

60. Zhao L, Chen Y, Tang R, Li Q, Gong J, Huang A. . Inflammatory stress exacerbates hepatic cholesterol accumulation via increasing cholesterol uptake and de novo synthesis. 2011;26:875-83

Cholesterol: Synthesis, Metabolism, Regulation

 13. Wang DQ. Regulation of intestinal cholesterol absorption.  2007;69:221-48

The rate limiting step in cholesterol synthesis ..

As eukaryotic genes mediating lipid metabolism, the expression of LDLR is also under intricate regulation at both the transcriptional and posttranscriptional levels, which are mediated through precise signalling pathways (Fig.). Cholesterol and its derivatives, as well as nonsterol factors, including inflammation mediator, growth factors, certain hormones, glucose and its metabolites are able to regulate LDLR expression[, ].

the rate-determining step of cholesterol synthesis

Cholesterol is an insoluble lipid molecule that plays a critical role in the structure and function of membrane bilayers. Membrane cholesterol contents that are either too high or too low are detrimental to cell function. When present in excess amounts in cells, cholesterol becomes toxic. Certainly, cholesterol-induced cytotoxicity represents a key initiating event leading to the development of atherosclerotic cardiovascular disease. Cholesterol is also used as a substrate for steroid hormone biosynthesis. Virtually all cells are capable of synthesizing their full complement of cholesterol, despite the capacity of the gastrointestinal tract to absorb large quantities. However, only hepatocytes within the liver are capable of degrading cholesterol and eliminating it in large quantities.

The uptake of exogenous cholesterol by cells results in a marked suppression of endogenouscholesterol synthesis.
Monogenic disorders of the cholesterol biosynthesis pathways and the loci that harbor the causative mutations.

Cholesterol Biosynthesis – Atorvastatin - Tufts University

26. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. 2002;109:1125-31

The majority of cholesterol utilized by healthy adults is synthesized in the liver, ..

Cholesterol biosynthesis regulation and protein changes …

The assembly of VLDL begins inside the rough endoplasmic reticulum of hepatocytes, at the site of translation. As the peptide is synthesized by membrane bound ribosomes, it is sent through a protein channel into the cytoplasm. Meanwhile, the aforementioned MTP binds the precursor peptide and recruits a small amount of triglycerides, phospholipids, and cholesteryl esters, allowing ApoB-100 to fold around a small lipid core (). Next, the bulk of VLDL triglycerides are transferred into the precursor particle, and the now larger precursor (sometimes referred to as VLDL2) is sorted to the Golgi apparatus. Evidence for a two-step maturation system up to this point is given by experiments using Brefeldin A (BFA), which inhibits only the transition into VLDL2, and not the initial lipidation of ApoB-100 (). BFA selectively inhibits the ADP-ribosylation factor (ARF) protein, suggesting that ARF is a critical factor in VLDL assembly (). Once in the Golgi, additional lipids are recruited to form the mature VLDL particle, but the mechanism behind this behavior is not yet clear. However, it is certain that the fatty acids used for the synthesis of VLDL are derived from triglycerides stored in cytosolic lipid droplets (), so it is likely that the concentration of these lipids is the rate limiting property of VLDL biogenesis.

21/12/2017 · Kinetic Mechanisms of Cholesterol Synthesis: ..

as alternative drug targets to control cholesterol synthesis.

SR-BI is most notorious for catalyzing uptake of cholesterol from lipid-rich HDL particles into hepatocytes, where it is converted into bile acids. The mechanism of HDL clearance is distinct from ABCA1 mediated cholesterol efflux and low density lipoprotein receptor endocytosis in that internalization of the entire particle does not occur, but rather cholesteryl esters are selectively taken into tissues (). In this way, mature α-HDL can quickly be recycled back into lipid-poor pre-β-HDL, and RCT can start again. Affinity of lipoprotein/SR-BI interaction is complex and highly related to apolipoprotein composition and particle geometry. SR-BI binds both LDL and HDL; however, preference is strongest for lipoproteins containing ApoA1, which it binds to tightly (). In fact, three HDL associated apolipoproteins, ApoA1, ApoA2, and ApoC3, each interact with SR-BI, and increase affinity for cholesterol movement ().