Cholesterol-associated LocusEHBP1Protects against NASH Fibrosis

Abstract

Hepatic 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 decreased EHBP1, a novel GWAS locus associated with LDL- cholesterol, and that the EHBP1 rs10496099 T>C variant in NASH patients is associated with decreased hepatic EHBP1 expression 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 TNFa/PPARa 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, including SORT1, PCSK9, and LDLR, but also elucidate a novel interplay between inflammation and EHBP1- mediated cholesterol metabolism.