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Elucidation of SIRT-1/PGC-1α-associated mitochondrial dysfunction and autophagy in nonalcoholic fatty liver disease
Yan Jiang1,2, Duankai Chen2, Qiming Gong2
1Medical College of Guangxi University, Nanning, 530004, Guangxi, China.
Background:
Nonalcoholic fatty liver disease (NAFLD) can lead to chronic liver diseases associated with mitochondrial damages. However, the exact mechanisms involved in the etiology of the disease are not clear.
Methods:
To gain new insights, the changes affecting sirtuin 1 (SIRT-1) during liver fat accumulation was investigated in a NAFLD mouse model. In addition, the in vitro research investigated the regulation operated by SIRT-1 on mitochondrial structures, biogenesis, functions, and autophagy.
Results:
In mice NAFLD, high-fat-diet (HFD) increased body weight gain, upregulated serum total cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, blood glucose, insulin levels, and liver malondialdehyde, and decreased liver superoxide dismutase activity. In liver, the levels of SIRT-1 and peroxisome proliferator-activated receptor-gamma coactivator -1α (PGC-1α) decreased. The expression of peroxisome proliferator-activated receptor-α and Beclin-1 proteins was also reduced, while p62/SQSTM1 expression increased. These results demonstrated SIRT-1 impairment in mouse NAFLD. In a well-established NAFLD cell model, exposure of the HepG2 hepatocyte cell line to oleic acid (OA) for 48 h caused viability reduction, apoptosis, lipid accumulation, and reactive oxygen species production. Disturbance of SIRT-1 expression affected mitochondria. Pre-treatment with Tenovin-6, a SIRT-1 inhibitor, aggravated the effect of OA on hepG2, while this effect was reversed by CAY10602, a SIRT-1 activator. Further investigation demonstrated that SIRT-1 activity was involved in mitochondrial biogenesis through PGC-1α and participated to the balance of autophagy regulatory proteins.
Conclusion:
In conclusion, in high-fat conditions, SIRT-1 regulates multiple cellular properties by influencing on mitochondrial physiology and lipid autophagy via the PGC-1α pathway. The SIRT-1/PGC-1α pathway could be targeted to develop new NAFLD therapeutic strategies.
Insights
Sirtuin 1 (SIRT-1) impairment is observed in nonalcoholic fatty liver disease (NAFLD) mouse models, affecting mitochondrial function and lipid autophagy. Targeting the SIRT-1/PGC-1α pathway offers potential for new NAFLD therapies.
Area of Science:
- Molecular Biology
- Hepatology
- Mitochondrial Biology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is linked to mitochondrial damage, but underlying mechanisms remain unclear.
- Investigating the role of sirtuin 1 (SIRT-1) in NAFLD pathogenesis is crucial for understanding disease progression.
Purpose of the Study:
- To investigate changes in SIRT-1 during liver fat accumulation in a NAFLD mouse model.
- To explore SIRT-1's regulatory role in mitochondrial biogenesis, function, and autophagy in vitro.
Main Methods:
- A high-fat diet (HFD) induced NAFLD in mice to assess metabolic and liver parameters.
- In vitro studies utilized HepG2 cells exposed to oleic acid (OA) to model NAFLD.
- SIRT-1 modulation using inhibitors (Tenovin-6) and activators (CAY10602) evaluated effects on cellular processes.
Main Results:
- HFD-induced NAFLD in mice showed decreased SIRT-1 and PGC-1α levels, alongside impaired mitochondrial and autophagy markers.
- OA exposure in HepG2 cells reduced viability, increased apoptosis, and impaired mitochondrial function, effects modulated by SIRT-1 activity.
- SIRT-1 regulates mitochondrial biogenesis via PGC-1α and influences autophagy-related protein balance.
Conclusions:
- SIRT-1 plays a critical role in regulating cellular functions, mitochondrial physiology, and lipid autophagy under high-fat conditions via the PGC-1α pathway.
- The SIRT-1/PGC-1α pathway represents a promising therapeutic target for developing novel strategies against NAFLD.
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