PuSH - Publication Server of Helmholtz Zentrum München: Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis.

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Sachdev, V.* ; van Loon, N.M.* ; Kingma, J.* ; Ottenhoff, R.* ; Tan, J.M.E.* ; van den Berg, M.* ; Duijst, S.* ; Jongejan, A.* ; Levels, J.H.M.* ; Rensen, P.C.N.* ; Kooijman, S.* ; de Boer, J.F.* ; Kuipers, F.* ; Kuentzel, K.B.* ; Kratky, D.* ; Kwon, Y.* ; Zeigerer, A. ; Hendrix, S.* ; Zelcer, N.*

Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis.

Mol. Metab. 108:102379 (2026)

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	Open Access Gold

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Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, steatohepatitis (MASH), feature excessive hepatic fat accumulation, yet the relative contributions of dietary vs. endogenous fats and their interactions has remained enigmatic. Here, we identify the endoplasmic reticulum–associated E3 ubiquitin ligase MARCHF6 as a pivotal regulator of hepatic lipid metabolism. Global or hepatocyte-specific deletion of Marchf6 induced spontaneous accumulation of triglycerides and cholesteryl esters under chow-fed conditions, revealing a cell-autonomous hepatic defect independent of caloric excess. Loss of MARCHF6 stabilized its substrate squalene epoxidase (SQLE), enhancing sterol pathway flux while concomitantly activating the SREBP1-associated lipogenic transcriptional program and increasing lipoprotein clearance. Accordingly, lipidomic analyses demonstrated remodeling of the hepatic lipidome towards polyunsaturated, long-chain neutral lipids, consistent with increased lipogenesis-driven NADPH consumption. In line with this, pharmacological inhibition of the oxidative pentose phosphate pathway reduced lipid accumulation in MARCHF6-deficient human hepatocytes. Congruently, transcriptomic data from human MASLD/MASH patients revealed reduced hepatic MARCHF6 expression alongside an increase in that of the lipogenic genes SREBF1, FASN, and SCD1. Overall, these data establish MARCHF6 as a multifaceted gatekeeper that integrates sterol turnover, NADPH usage, and lipogenesis to maintain hepatic lipid homeostasis.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Lipogenesis ; Marchf6 ; Masld ; Nadph ; Post-transcriptional Regulation ; Srebp; Element-binding Protein; Leucine Zipper Protein; Gene-expression; Confers Susceptibility; Wide Association; Sterol; Transcription; Degradation; Cholesterol; Enzyme

ISSN (print) / ISBN 2212-8778

e-ISSN 2212-8778

Journal Molecular Metabolism

Quellenangaben Volume: 108, Article Number: 102379

Publisher Elsevier

Publishing Place Amsterdam

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants NWO ZonMW
NWO ENW grant
Netherlands Organisation for Scientific Research (NWO)
Austrian Science Fund (FWF)
Noaber Foundation (Lunteren, The Netherlands)
Amsterdam Cardiovascular Science Talent Grant
Amsterdam UMC Bridging