Cholesterol and bile acid-mediated regulation of autophagy in fatty liver diseases and atherosclerosis

Abstract

Liver is the major organ that regulates whole body cholesterol metabolism. Disrupted hepatic cholesterol homeostasis contributes to the pathogenesis of nonalcoholic steatohepatitis, dyslipidemia, atherosclerosis, and cardiovascular diseases. Hepatic bile acid synthesis is the major catabolic mechanism for cholesterol elimination from the body. Furthermore, bile acids are signaling molecules that regulate liver metabolism and inflammation. Autophagy is a highly-conserved lysosomal degradation mechanism, which plays an essential role in maintaining cellular integrity and energy homeostasis. In this review, we discuss emerging evidence linking hepatic cholesterol and bile acid metabolism to cellular autophagy activity in hepatocytes and macrophages, and how these interactions may be implicated in the pathogenesis and treatment of fatty liver disease and atherosclerosis.

Keywords: Enterohepatic circulation; Hepatocyte; Hyperlipidemia; Liver injury; Macrophage; Nuclear receptor; Nutrient signaling.

Figure 1. Bile acid synthesis and enterohepatic circulation

Hepatocytes acquire cholesterol via de novo synthesis and receptor-mediated endocytosis of cholesterol-rich lipoproteins. Hepatocytes eliminate cholesterol via bile acid synthesis and biliary secretion of cholesterol via ABCG5/ABCG8. Bile acids are synthesized from cholesterol in hepatocytes. CYP7A1 catalyzes the first and rate-limiting step in cholesterol conversion into bile acids. Bile acids are secreted into the bile via BSEP and subsequently released into the small intestine. The majority of bile acids is re-absorbed into the enterocytes via ASBT and transported back to the liver via portal circulation. Basolateral NTCP transports conjugated bile acids into the hepatocytes. Bile acids in the hepatocytes activate FXR to inhibit CYP7A1. Bile acids in the small intestine activate FXR to induce FGF15, which binds and activates FGFR4 to inhibit CYP7A1 partially via ERK signaling.

Figure 2. Role of autophagy in cholesterol metabolism in hepatocytes

Lysosome-derived free cholesterol (FC) can be transported to the plasma membrane, effluxed via ABCA1 and ABCG1 to HDL, or converted to cholesterol ester (CE) or enter the bile acid synthesis pathway in the ER. CE can be incorporated into VLDL for secretion into the blood, or stored in the lipid droplets (LD). Neutral cholesterol ester hydrolases (CEH) hydrolyze CE in the lipid droplets and the resulting FC can re-enter the cellular FC pool. In addition, autophagy delivers CE from the lipid droplets to the lysosomes where lysosomal acid lipase (LAL) converts CE to FC. Excessive cholesterol accumulation disrupts intrahepatic cholesterol homeostasis, resulting in elevated FC content in the “cholesterol poor” intracellular organelles such as the mitochondria and the ER. In addition, FC accumulation in the lysosomes impairs lysosomal function, resulting in delayed autophagosome clearance. Increased bile acids also inhibit autophagy gene expression. Blocking intestine bile acid re-uptake such as by bile acid sequestrants can decrease hepatic bile acid signaling. As a result, induction of CYP7A1 causes increased ER cholesterol catabolism, relative ER cholesterol depletion and SREBP-2 activation, leading to induction of LDLR and HMGCR expression to replenish cellular cholesterol. Removal of bile acids and stimulation of cholesterol catabolism induce autophagic flux, which promotes acidic CE hydrolysis to help replenish cellular FC pool.

Figure 3. Regulation of macrophage cholesterol metabolism

Macrophages acquire cholesterol via LDLR-mediated uptake of LDL and scavenger receptor (CD36)-mediated uptake of oxLDL. Endocytosed cholesterol-rich particles are delivered to the lysosomes where lysosomal acid lipase (LAL) converts CE to FC. FC can be delivered to the plasma membrane or to the ER where FC is converted to CE by ACAT. Excessive CE is stored in the lipid droplets (LD). Neutral cholesterol ester hydrolases (CEH) can convert lipid droplet CE back to FC for either efflux via the ABCA1 and ABCG1 to HDL or for re-esterification by ACAT in the ER. Autophagy delivers lipids from lipid droplets to the lysosomes and thus contributes to acidic CE hydrolysis. FC generated in the lysosomes can also be effluxed to HDL via ABCA1 and ABCG1. Lipid overloading can induce lysosomal stress and dysfunction. This may impair autophagy by causing autophagosome/lysosome fusion defects or delayed autophagosome cargo clearance. Lysosomal permeabilization and content release can also activate inflammasomes and cytokine secretion. As cellular compensatory mechanisms, intracellular cholesterol accumulation and subsequently elevated oxysterols activate LXR to transcriptionally induce ABCA1 and ABCG1. Furthermore, lysosomal stress can cause TFEB to translocate to the nucleus where TFEB induces genes to promote lysosomal biogenesis and autophagy.