Cholesterol and Lipoprotein Metabolism
Early Career Committee Contribution
Although cholesterol is necessary to maintain cellular integrity and is an essential precursor for steroid hormones and bile acids, an elevated concentration of circulating cholesterol is a strong risk factor for cardiovascular diseases (CVDs), which accounts for ≈1 of every 3 deaths in the United States.1 In recognition of National Cholesterol Month, this article highlights recent studies published in ATVB focused on the regulation of hepatic cholesterol metabolism and reverse cholesterol transport (RCT), the pathophysiological effect of hypercholesterolemia, and therapeutic strategies to counteract hypercholesterolemia and its associated CVD.
Hepatic Cholesterol Metabolism
The liver plays a central role in whole-body cholesterol homeostasis, thus perturbations in hepatic cholesterol metabolism can result in hypercholesterolemia. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and is a target of the low-density lipoprotein (LDL)–lowering drugs statins. However, mice with liver-specific deficiency of HMGCR developed hepatic steatosis, despite mildly decreased hepatic cholesterol levels, which was attributable to compensatory increases in triglyceride and fatty acid synthesis.2 The regulation of hepatic cholesterol synthesis is also regulated by the uptake of different lipoprotein classes. In hamster hepatocytes, cholesterol synthesis was not affected by LDL uptake but was significantly reduced by uptake of other lipoprotein particles.3
The secretion of hepatic apolipoprotein B (apoB)–containing lipoproteins and the clearance of circulating apoB-containing lipoproteins through hepatic lipoprotein receptors are essential to maintain hepatic and whole-body cholesterol homeostasis. It was found that a large portion of LDL cholesterol (LDL-C) internalized by hepatocytes was secreted in very-low density lipoprotein (VLDL) or high-density lipoprotein (HDL) without reaching equilibrium with the regulatory pool.3 In a rat hepatoma cell line, an adaptor protein, kelch-like protein 12, was colocalized with apoB100, facilitating the endoplasmic reticulum exit and secretion of apoB100-VLDL particles. Kelch-like protein 12 knockdown, therefore, …