Cholesterol-associated LocusEHBP1Protects against NASH Fibrosis

Abstract

SUMMARYHepatic free cholesterol contributes to fibrosis in nonalcoholic steatohepatitis (NASH), but how hepatic cholesterol metabolism becomes dysregulated in NASH is not completely understood. We show here that human fibrotic NASH livers have decreasedEHBP1, a novel GWAS locus associated with LDL-cholesterol, and that theEHBP1rs10496099 T>C variant in NASH patients is associated with decreased hepaticEHBP1expression and augmented NASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases NASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in NASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and NASH fibrosis by uncovering the interaction between EHBP1 and other cholesterol–related loci, includingSORT1,PCSK9, andLDLR, but also elucidate a novel interplay between inflammation and EHBP1-mediated cholesterol metabolism.HighlightsHepatic EHBP1 is reduced in human and mouse fibrotic NASHEHBP1rs10496099 T>C is associated with decreased hepatic EHBP1 and augmented NASHEHBP1 reduces LDLR, cholesterol uptake, and TAZ in hepatocytesEHBP1 promotes sortilin-mediated PCSK9 secretion in hepatocytesTNFα suppresses EHBP1 expression in hepatocytes