Cholesterol overload in macrophages drives metabolic dysfunction-associated steatohepatitis via inhibiting 7-dehydrocholesterol reductase in mice.

Autor: Li X; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China., Wang K; Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China., Sun Y; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China.; School of Public Health, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China., Wang Y; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China., Wu J; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China., Dang Y; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China., Li M; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China. limengsmile1@163.com., Zhou W; Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China. zhouwenjun@shutcm.edu.cn.; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, China. zhouwenjun@shutcm.edu.cn.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Nov 29; Vol. 22 (1), pp. 1085. Date of Electronic Publication: 2024 Nov 29.
DOI: 10.1186/s12967-024-05905-1
Abstrakt: Background: Dietary cholesterol promotes metabolic dysfunction-associated steatohepatitis (MASH), with hepatic macrophages central to disease pathology. However, the mechanisms by which cholesterol-loaded macrophages influence MASH remain unclear.
Methods: In this study, mice were fed a cholesterol-rich choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Hepatic cholesterol levels, inflammatory markers, and pro-inflammatory macrophage polarization were assessed. In vitro studies examined the impact of cholesterol on macrophage polarization, identifying 7-dehydrocholesterol reductase (DHCR7) as a key cholesterol- and inflammation-responsive enzyme. DHCR7 expression in macrophages from MASH patients and model mice was evaluated. Functional studies involving in vitro knockdown and overexpression experiments, were complemented using myeloid-specific DHCR7 knockout mice. RNA sequencing was performed on liver tissues from wild-type and DHCR7 knockout mice to identify affected signaling pathways.
Results: CDAHFD-fed mice exhibited local cholesterol accumulation and a pro-inflammatory macrophage phenotype in the liver. Cholesterol overload in vitro promoted M1 polarization and liver inflammation, reversible by simvastatin. DHCR7 expression, responded to cholesterol and polarization state, was downregulated in M1-polarized and hepatic macrophages from MASH patients and mice. DHCR7 suppression promoted pro-inflammatory phenotype, while its overexpression showed anti-inflammatory effects. Myeloid-specific DHCR7 deficiency in CDAHFD-fed mice worsened liver inflammation and pro-inflammatory macrophage infiltration. RNA sequencing identified the phosphoinositide 3-kinase (PI3K) pathway in DHCR7-regulated effects, with DHCR7-PI3K axis activation mitigating cholesterol-driven inflammation.
Conclusions: These findings unveil novel mechanistic insights into MASH pathogenesis, suggesting targeting macrophage-specific DHCR7 activation may offer a promising therapeutic strategy for MASH.
Competing Interests: Declarations. Ethics approval and consent to participate: Approval: The animal experiments in this study were approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese medicine. Consent for publication: All authors confirm their consent for publication the manuscript. Competing interests: The authors declare that they have no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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