Function of the Endolysosomal Network in Cholesterol Homeostasis and Metabolic Associated Fatty Liver Disease (MAFLD)

BACKGROUND: Metabolic associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease, has become the leading cause of chronic liver disease worldwide. Besides hepatic accumulation of triglycerides, dysregulated cholesterol metabolism is an important contributor to the pathogenesis of MAFLD. Maintenance of cholesterol homeostasis is highly dependent on cellular cholesterol uptake, and subsequently cholesterol transport to other membrane compartments, such as the endocytic reticulum (ER). SCOPE OF REVIEW: The endolysosomal network is key for regulating cellular homeostasis and adaptation, and emerging evidence has shown that the endolysosomal network is crucial to maintain metabolic homeostasis. In this review, we will summarize our current understanding of the role of the endolysosomal network in cholesterol homeostasis and its implications in MAFLD pathogenesis. MAJOR CONCLUSIONS: Although multiple endolysosomal proteins have been identified in the regulation of cholesterol uptake, intracellular transport, and degradation, their physiological role is incompletely understood. Further research should elucidate their role in controlling metabolic homeostasis and development of fatty liver disease

The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance

The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1. Hepatic WASH ablation also reduced the surface levels of scavenger receptor class B type I and, concomitantly, selective uptake of HDL cholesterol into the liver. Furthermore, we found that WASHC1 deficiency increases LDLR proteolysis by the inducible degrader of LDLR, but does not affect proprotein convertase subtilisin/kexin type 9-mediated LDLR degradation. Remarkably, however, loss of hepatic WASHC1 may sensitize LDLR for proprotein convertase subtilisin/kexin type 9-induced degradation. Altogether, these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes