Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis.

Autor:	Kleiboeker B; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., He A; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Tan M; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Lu D; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Hu D; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Liu X; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Goodarzi P; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Hsu FF; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA., Razani B; Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA., Semenkovich CF; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Lodhi IJ; Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: ilodhi@wustl.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Apr; Vol. 82, pp. 101913. Date of Electronic Publication: 2024 Mar 07.
DOI:	10.1016/j.molmet.2024.101913
Abstrakt:	Objective: Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis. Methods: To explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and 14 C-malonyl CoA allowed us to measure de novo lipogenic activity in adipose tissue of these mice. In vitro cell culture models were used to elucidate the mechanism of cellular responses to PexRAP deletion. Results: Adipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance. Conclusions: These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation. Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists. (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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