Liver-specific overexpression of SIRT3 enhances oxidative metabolism, but does not impact metabolic defects induced by high fat feeding in mice
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The mitochondrial enzyme SIRT3 is an NAD+-dependent deacetylase important in cell metabolism, and a decline in its protein expression or activity has been linked with insulin resistance in obesity, ageing and type 2 diabetes. While studies in SIRT3 knockout mice have dramatically improved our understanding of the function of SIRT3, the impact of increasing SIRT3 levels remains under-examined. In this study we investigated the effects of liver-specific SIRT3 overexpression in mice on mitochondrial function and metabolic profile in both isolated hepatocytes and in vivo. Primary hepatocytes overexpressing SIRT3 displayed increased oxygen consumption and a reduction in triglyceride accumulation. In mice with hepatic SIRT3 overexpression, increased fasting β-hydroxybutyrate levels were observed, coupled with an increase in oxygen consumption in isolated mitochondria and increased substrate utilization in liver homogenates. However, metabolic profiling of mice exposed to either chow or high-fat diet revealed no effect of hepatic SIRT3 overexpression on glucose tolerance, body composition or tissue triglyceride accumulation. These findings suggest limited whole-body benefit of increasing hepatic SIRT3 during the development of diet-induced insulin resistance.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Biochemical and Biophysical Research Communications |
| Vol/bind | 607 |
| Sider (fra-til) | 131-137 |
| Antal sider | 7 |
| ISSN | 0006-291X |
| DOI | |
| Status | Udgivet - 2022 |
| Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
In the ex vivo model of isolated primary hepatocytes, SIRT3 overexpression caused an increase in oxygen consumption, supporting the reported function of SIRT3 to increase the activity of a variety of mitochondrial enzymes, including those of oxidative phosphorylation and fatty acid metabolism [4,9,22,26,27]. Further support for this role of SIRT3 in the current study is the elevated oxidation of 2–14C pyruvate, which releases the labelled 14C upon metabolism in the TCA cycle, as well as the increase in palmitoylcarnitine-supported respiration in liver mitochondria under fasted conditions, a state known to induce maximal activation of SIRT3 activity [28]. Similar findings of increased respiration have been reported in HEK293 cells stably transfected with SIRT3 [29], while deletion of SIRT3 is linked with reduced mitochondrial respiratory capacity [4].We thank the Biological Testing Facility at the Garvan Institute for assistance with animal care. This work was supported by the National Health and Medical Research Council of Australia (NHMRC; APP1043779). BO was supported by a PhD scholarship (APP1017534) and GJC by a research fellowship from the NHMRC (APP1003313). NT was supported by an Australian Research Council Future Fellowship (FT120100371).
Funding Information:
We thank the Biological Testing Facility at the Garvan Institute for assistance with animal care. This work was supported by the National Health and Medical Research Council of Australia ( NHMRC ; APP1043779 ). BO was supported by a PhD scholarship ( APP1017534 ) and GJC by a research fellowship from the NHMRC ( APP1003313 ). NT was supported by an Australian Research Council Future Fellowship ( FT120100371 ).
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