Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice.

Abstract

Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria from proteotoxicity under various types of stress. In this study, we investigated whether HSP60 could ameliorate experimental high-fat diet (HFD)-induced obesity and hepatitis and explored the potential mechanism in mice. The results uncovered that HSP60 gain not only alleviated HFD-induced body weight gain, fat accumulation, and hepatocellular steatosis, but also glucose tolerance and insulin resistance according to intraperitoneal glucose tolerance testing and insulin tolerance testing in HSP60 transgenic (HSP60Tg) compared to wild-type (WT) mice by HFD. Furthermore, overexpression of HSP60 in the HFD group resulted in inhibited release of mitochondrial dsRNA (mt-dsRNA) compared to WT mice. In addition, overexpression of HSP60 also inhibited the activation of toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and phosphorylated-interferon regulatory factor 3 (p-IRF3), as well as inflammatory biomarkers such as mRNA of il-1β and il-6 expression in the liver in response to HFD. The in vitro study also confirmed that the addition of HSP-60 mimics in HepG2 cells led to upregulated expression level of HSP60 and restricted release of mt-dsRNA, as well as downregulated expression levels of TLR3, MDA5, and pIRF3. This study provides novel insight into a hepatoprotective effect, whereby HSP60 inhibits the release of dsRNA to repress the TLR3/MDA5/pIRF3 pathway in the context of NAFLD or hepatic inflammation. Therefore, HSP60 may serve as a possible therapeutic target for improving NAFLD.

• Authors: Ying-Hsien Huang, Feng-Sheng Wang, Pei-Wen Wang, Hung-Yu Lin, Sheng-Dean Luo, Ya-Ling Yang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 1 (Jan 05 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35009003 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Chaperonin 60
• RNA, Double-Stranded
• Toll-Like Receptor 3
• Glucose

Topics

• Adipose Tissue (metabolism)
• Animals
• Biomarkers
• Body Weight
• Chaperonin 60 (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Disease Susceptibility
• Fluorescent Antibody Technique
• Gene Expression Regulation
• Glucose (metabolism)
• Hepatitis (etiology, metabolism, pathology)
• Immunohistochemistry
• Insulin Resistance
• Lipid Metabolism
• Mice
• Mitochondria (genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (etiology, metabolism, pathology)
• RNA, Double-Stranded (genetics)
• Toll-Like Receptor 3 (metabolism)