SIRT1 Regulates Hepatic Vldlr Levels

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 May 28

PMID 38807218

Authors

Mona Peyman

Anna Babin-Ebell

Rosalia Rodriguez-Rodriguez

Matilde Rigon

David Aguilar-Recarte

Joan Villarroya

Anna Planavila

Francesc Villarroya

Xavier Palomer

Emma Barroso

Manuel Vazquez-Carrera

Affiliations

Soon will be listed here.

Abstract

Background: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD()-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins.

Methods: Rats fed with fructose in drinking water, Sirt1 mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used.

Results: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1 mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin.

Conclusions: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.

Citing Articles

Metabolic-Associated Fatty Liver Disease: The Influence of Oxidative Stress, Inflammation, Mitochondrial Dysfunctions, and the Role of Polyphenols.

Tauil R, Golono P, de Lima E, de Alvares Goulart R, Landgraf Guiguer E, Bechara M Pharmaceuticals (Basel). 2024; 17(10).

PMID: 39458995 PMC: 11510109. DOI: 10.3390/ph17101354.

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