Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis
Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved..
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 14C-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Molecular metabolism - 82(2024) vom: 06. Apr., Seite 101913 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kleiboeker, Brian [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.04.2024 Date Revised 04.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molmet.2024.101913 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM369483049 |
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| 245 | 1 | 0 | |a Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis |
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| 500 | |a Date Revised 04.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 14C-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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Adipose tissue | |
| 650 | 4 | |a Cholesterol | |
| 650 | 4 | |a De novo lipogenesis | |
| 650 | 4 | |a Diabetes | |
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| 650 | 7 | |a EC 2.3.1.23 |2 NLM | |
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| 700 | 1 | |a He, Anyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Dongliang |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Donghua |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xuejing |e verfasserin |4 aut | |
| 700 | 1 | |a Goodarzi, Parniyan |e verfasserin |4 aut | |
| 700 | 1 | |a Hsu, Fong-Fu |e verfasserin |4 aut | |
| 700 | 1 | |a Razani, Babak |e verfasserin |4 aut | |
| 700 | 1 | |a Semenkovich, Clay F |e verfasserin |4 aut | |
| 700 | 1 | |a Lodhi, Irfan J |e verfasserin |4 aut | |
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