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SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1?-LIPIN 1 pathway and increasing CD36 through Nrf2.

ABSTRACT: BACKGROUND:Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). METHODS:Studies were conducted in wild-type (WT) and Sirt3-/- mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. RESULTS:Sirt3-/- mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) ? and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPAR? co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1? (HIF-1?). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3-/- mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. CONCLUSION:These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Video abstract.

SUBMITTER: Barroso E

PROVIDER: S-EPMC7488148 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2.

Barroso Emma E Rodríguez-Rodríguez Rosalía R Zarei Mohammad M Pizarro-Degado Javier J Planavila Anna A Palomer Xavier X Villarroya Francesc F Vázquez-Carrera Manuel M

Cell communication and signaling : CCS 20200910 1

<h4>Background</h4>Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD<sup>+</sup>-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD).<h4>Methods</h4>Studies were conducted in wild-type (WT) and Sirt3<sup>-/-</sup> mice fed a standard diet or a HFD and in SIRT3-knockdown huma ...[more]

PMID: 32912335

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SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1?-LIPIN 1 pathway and increasing CD36 through Nrf2.

Publications

SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2.

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