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Sachdev, V.; Loon, N.M. van; Kingma, J.; Ottenhoff, R.; Tan, J.M.E.; Berg, M. van den; ... ; Zelcer, N. (2026)

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

Article / Letter to editor
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 hepatocytespecific 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...Show moreMetabolic 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 hepatocytespecific 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. (c) 2026 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Show less
MASLD
SREBP
MARCHF6
Lipogenesis
Post-transcriptional regulation
NADPH
All authors
Sachdev, V.; Loon, N.M. van; Kingma, J.; Ottenhoff, R.; Tan, J.M.E.; Berg, M. van den; Duijst, S.; Jongejan, A.; Levels, J.H.M.; Rensen, P.C.N.; Kooijman, S.; Boer, J.F. de; Kuipers, F.; Kuentzel, K.B.; Kratky, D.; Kwon, Y.; Zeigerer, A.; Hendrix, S.; Zelcer, N.
Date
2026-05-11
Journal
Molecular Metabolism
Volume
108
DOI
doi:10.1016/j.molmet.2026.102379