SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity

Abstract

SIRT3 is the primary mitochondrial deacetylase that modulates mitochondrial metabolic and oxidative stress regulatory pathways. However, its role in response to nutrient excess remains unknown. Thus, we investigated SIRT3 regulation of the electron transfer chain and evaluated the role of SIRT3 in hepatic lipotoxic stress. SIRT3 depleted HepG2 cells shows diffuse disruption in mitochondrial electron transfer chain functioning, a concurrent reduction in the mitochondrial membrane potential, and excess basal reactive oxygen species levels. As this phenotype may predispose to increased lipotoxic hepatic susceptibility we evaluated the expression of SIRT3 in murine liver following chronic high-fat feeding. In this nutrient-excess model SIRT3 transcript and protein levels are downregulated in parallel with increased hepatic fat storage and oxidative stress. Palmitate was used to investigate lipotoxic susceptibility in SIRT3 knockout mouse primary hepatocytes and SIRT3 siRNA depleted HepG2 cells. Under SIRT3 deficient conditions palmitate enhances reactive oxygen species and increases hepatocyte cell death. Reconstitution of SIRT3 levels and/or treatment with N-acetylcysteine ameliorates these adverse effects. In conclusion SIRT3 functions to ameliorate hepatic lipotoxicity, although paradoxically, exposure to high-fat downregulates this adaptive program in the liver. This SIRT3-dependent lipotoxic susceptibility is possibly modulated, in part, by SIRT3 mediated control of electron transfer chain flux.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…As previously mentioned, SIRT3 expression and activity decline in response to high-fat feeding (9,59,77,111), and mice lacking SIRT3 show accelerated obesity, insulin resistance, hyperlipidemia, and hepatic steatosis when fed an HFD over a prolonged period (59). In this context, SIRT3-deficient mice fed a HFD expressed elevated levels of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) (59).…”

“…SIRT3 expression was higher in peripheral blood mononuclear cells from individuals homozygous for this variant (4). Conversely, SIRT3 expression and activity decline in response to high-fat feeding (9,59,77,111), in insulin resistance (174), and in human subjects with the metabolic syndrome (59). Mice with germline ablation of Sirt3 have no grossly apparent phenotype under nonstress conditions (91).…”

“…Various studies have revealed that SIRT3 deacetylates multiple ETC proteins to enhance energy production and improve ETC efficiency, such as NDUFA9 (complex I), SDHA (complex II), and the ATP synthase subunit b (complex V) (1,9,27,40,77,79,125). Moreover, the activities of complexes III and IV are significantly reduced in Sirt3-null mice under high-fat feeding conditions (77).…”

Mitochondrial Metabolism, Sirtuins, and Aging

“…In keeping with its role as the final common denominator in mitochondrial energy production, numerous proteins in the electron transport chain have been shown to be directly deacetylated by Sirt3. Sirt3 activation has been shown to increase oxidative phosphorylation (Ahn et al 2008;Bao et al 2010a;Cimen et al 2010) and to deacetylate and activate enzymes in complexes I and II of the electron transport chain (Ahn et al 2008;Cimen et al 2010;Finley et al 2011;Kendrick et al 2011), with additional deacetylation of proteins in complex V (Schlicker et al 2008;Bao et al 2010b). …”

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

“…Because chronic high fat feeding is linked to the down-regulation of SIRT3 (11)(12)(13) and to increased mitochondrial protein acetylation, we questioned whether an additional level of regulation linking SIRT3, elevated fatty acid levels, mitochondrial protein acetylation, and fat oxidation may be operational to account for some of these inconsistencies.…”