Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses

Abstract

The risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.

Soat2 ties cholesterol metabolism to β‐oxidation and glucose tolerance in male mice

“…The positive effects on adipose tissue and muscles also suggest that genetic depletion of Soat2 ameliorates the metabolic status of mice, beyond the observed diminished or complete resistance to hepatic steatosis. Our study strongly suggests specific inhibition of ACAT2 as an effective strategy to reduce liver lipid accumulation—a strategy with positive consequences beyond the cardiometabolic diseases as suggested by the recent finding that ACAT2 /SOAT2 increases the risk for NAFLD following hepatitis C virus infection [14].…”

“…Also, Soat2 −/− mice are resistant to dietary cholesterol-induced hepatic steatosis [12,13]. In humans, ACAT2/SOAT2chaperoned by apolipoprotein J-has recently been shown to facilitate the hepatic lipid accumulation following hepatitis C virus infection and nutrient stress [14]. Hence, ACAT2/SOAT2 increases the risk for NAFLD also after non-obese stress [14].…”

The interplay between lipid droplets and virus infection

“…HCV infection induces ApoJ expression and redistributes ApoJ from Golgi to encircle LDs, where ApoJ colocalizes with NS5A and core protein and stabilizes them, leading to enhanced HCV virion production 62 . ApoJ also binds to O‐acyltransferase 2 (SOAT2) to increase cholesteryl ester for lipid loads, contributing to stress‐induced steatosis 63 . Another apolipoprotein ApoE is associated with viral envelope glycoprotein E2 and plays a critical role in HCV virion maturation 64 .…”

Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition

“…The coding region of human ApoJ was cloned into p3xFLAG-CMV-14 and pEGFP-C1; [17] pHA-Ub was kindly provided by Professor Haizhen Zhu, Hunan University. The ApoJ R227Q and ApoJ R324L constructs were obtained by point mutation, and the coding region of mTOR and its corresponding domains were cloned into the pcDNA3.1-3xFlag expression vector provided by Tsingke Biotechnology Co., Ltd. (Changsha, China).…”

“…[14] On the other hand, nonsecreted intracellular ApoJ in response to extracellular stimuli is translocated to different subcellular fractions where ApoJ exerts different cellular functions. [15][16][17] Previously, our group showed that Golgiresident ApoJ is translocated to the Golgi-endoplasmic reticulum membrane contact site where ApoJ chaperones either viral proteins to facilitate the assembly of HCV particles or stabilizes sterol O-acyltransferase 2 (SOAT2) to induce LD accumulation. [16,17] Moreover, ApoJ participates in autophagosome biogenesis through maintaining LC3-Atg3 heterocomplex stability and promotes anticancer treatment resistance.…”