TOMM40 regulates hepatocellular and plasma lipid metabolism via an LXR-dependent pathway.

Autor:	Yang NV; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA., Chao JY; Department of Pediatrics, University of California, San Francisco, CA, USA., Garton KA; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA., Tran T; Department of Pediatrics, University of California, San Francisco, CA, USA., King SM; Department of Pediatrics, University of California, San Francisco, CA, USA., Orr J; Department of Pediatrics, University of California, San Francisco, CA, USA., Oei JH; Department of Pediatrics, University of California, San Francisco, CA, USA., Crawford A; Department of Pediatrics, University of California, San Francisco, CA, USA., Kang M; Electron Microscope Laboratory, University of California, Berkeley, CA, USA., Zalpuri R; Electron Microscope Laboratory, University of California, Berkeley, CA, USA., Jorgens DM; Electron Microscope Laboratory, University of California, Berkeley, CA, USA., Konchadi P; Department of Medicine, University of California, San Francisco, CA, USA., Chorba JS; Department of Medicine, University of California, San Francisco, CA, USA; Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA., Theusch E; Department of Pediatrics, University of California, San Francisco, CA, USA., Krauss RM; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA. Electronic address: ronald.krauss@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Dec; Vol. 90, pp. 102056. Date of Electronic Publication: 2024 Nov 01.
DOI:	10.1016/j.molmet.2024.102056
Abstrakt:	Objective: The gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. While human genetic variants near APOE and TOMM40 have been shown to be strongly associated with plasma lipid levels, a specific role for TOMM40 in lipid metabolism has not been established, and the present study was aimed at assessing this possibility. Methods: TOMM40 was knocked down by siRNA in human hepatoma HepG2 cells, and effects on mitochondrial function, lipid phenotypes, and crosstalk between mitochondria, ER, and lipid droplets were examined. Additionally, hepatic and plasma lipid levels were measured in mice following shRNA-induced knockdown of Tomm40 shRNA. Results: In HepG2 cells, TOMM40 knockdown upregulated expression of APOE and LDLR in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With TOMM40 knockdown, cellular triglyceride and lipid droplet content were increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining was significantly reduced by concomitant suppression of either LDLR or APOE. In contrast, cellular cholesterol content was reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, in vivo knockdown of TOMM40 in mice resulted in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis. Conclusions: These findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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