Cholesterol-Associated Locus EHBP1 Protects Against MASH Fibrosis

Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show here that human fibrotic MASH livers have decreased EHBP1, a novel GWAS locus associated with LDL cholesterol, and that the EHBP1 rs10496099 T>C variant in MASH patients is associated with decreased hepatic EHBP1 expression and with augmented MASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion by maintaining retromer homeostasis, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. Our novel therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the TNFa/PPARa pathway suppresses EHBP1 in MASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and MASH 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.

Note:
Funding Information: This work was supported, in part, by NIH grants R00DK115778, R01DK134610, R01HL167107, and R35GM147269, the Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, and the PhRMA Foundation Research Starter Grant in Translational Medicine (to B.Cai.); R01DK128289, R01DK121154, and P30CA196521 (to S.L.F.); R21HD106263 (to X.H.); R01DK136016 and AGA2020-13-03 (to S.W.); R01DK134011 and R00HL150233 (to O.R.); and R01HL167758 and R00HL145131 (to A.Y.J). Human liver samples were obtained from the Liver Tissue Cell Distribution System (University of Minnesota), funded by NIH contract HHSN276201200017C.

Declaration of Interests: The authors declare no competing interests.

Ethical Approval Statement: All procedures (mice) were performed according to protocols approved by the Animal Care and Use Committee of Icahn School of Medicine at Mount Sinai

All human studies were approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board and were conducted in accordance with National Institutes of Health and institutional guidelines for human subject research.

Keywords: Metabolic dysfunction-associated steatohepatitis (MASH), cholesterol, GWAS, Liver fibrosis, EHBP1, PCSK9, Sortilin, Retromer, TPT-260

Suggested Citation: Suggested Citation

Ma, Fanglin and Longo, Miriam and Huang, Xin and Meroni, Marica and Bhattacharya, Dipankar and Paolini, Erika and Cogliati, Bruno and Wang, Shuang and Wang, Xiaobo and Prakash, Satya and Mughal, Shama and Hussain, Syed and Anand, Sumit and Gupta, Neha and Zhu, Yiwei and Navarro-Corcuera, Amaia and Rom, Oren and Yurdagul, Arif and Wang, Liheng and Fried, Susan and Dongiovanni, Paola and Friedman, Scott and Cai, Bishuang, Cholesterol-Associated Locus EHBP1 Protects Against MASH Fibrosis. Available at SSRN: https://ssrn.com/abstract=4709532 or http://dx.doi.org/10.2139/ssrn.4709532

This version of the paper has not been formally peer reviewed.