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MicroRNA 29a alleviates mitochondrial stress in diet-induced NAFLD by inhibiting the MAVS pathway
Ya-Ling Yang1, Yuan-Ting Chuang2, Ying-Hsien Huang2
1Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan.
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder characterized by fat accumulation in the liver. This leads to aggravated hepatocyte inflammation due to impaired mitochondrial function, mitochondrial double-stranded RNA (mt-dsRNA) release, elevated oxidative stress, and reactive oxygen species (ROS) production. MicroRNA-29a (miR-29a) is used to reduce hepatic fibrosis in cases of cholestatic liver damage and lessen the severity of non-alcoholic steatohepatitis in animal studies by influencing mitochondrial protein balance. However, the effectiveness of miR-29a in diminishing mt-dsRNA-induced exacerbation of NAFLD remains poorly understood, particularly in the context of a Western diet (WD). Our results have found that mice with increased miR-29a levels and fed a WD showed notably decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, and low-density lipoprotein cholesterol levels. They also experienced less weight gain and lower final body and liver weights. In addition, overexpression of miR-29a reduced the severity of fibrosis, alleviated hepatic oxidative stress, misfolded protein aggregates, and the release of mt-dsRNA. Moreover, miR-29a attenuated the innate immune mitochondrial antiviral-signaling protein (MAVS) pathway response. In vitro, the research using HepG2 cells confirmed that miR-29a reduces MAVS expression and decreases the release of mt-dsRNA and superoxide initiated by palmitic acid (PA). Analysis of luciferase activity further established that the specific binding of miR-29a to the 3'UTR of MAVS led to a repression of its expression. In conclusion, these groundbreaking findings underscore the potential of miR-29a in improving the treatment of NAFLD and liver steatofibrosis by inhibiting the MAVS signaling pathway.
Insights
MicroRNA-29a (miR-29a) effectively combats non-alcoholic fatty liver disease (NAFLD) by reducing liver damage, inflammation, and fibrosis. This study shows miR-29a inhibits the MAVS pathway, offering a potential new treatment for NAFLD.
Area of Science:
- Hepatology
- Molecular Biology
- Mitochondrial Biology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by fat accumulation, leading to inflammation, oxidative stress, and mitochondrial dysfunction.
- Mitochondrial double-stranded RNA (mt-dsRNA) release exacerbates NAFLD pathogenesis.
- MicroRNA-29a (miR-29a) has shown promise in reducing liver fibrosis and non-alcoholic steatohepatitis severity, but its role in mt-dsRNA-induced NAFLD is unclear.
Purpose of the Study:
- To investigate the therapeutic potential of miR-29a in mitigating mt-dsRNA-induced NAFLD progression, particularly under a Western diet (WD).
- To elucidate the molecular mechanisms by which miR-29a influences NAFLD pathogenesis, focusing on the MAVS signaling pathway.
Main Methods:
- Mice with elevated miR-29a levels were fed a Western diet (WD).
- Biochemical markers (AST, ALT, cholesterol), body and liver weights, hepatic fibrosis, oxidative stress, protein aggregation, and mt-dsRNA release were assessed.
- In vitro studies using HepG2 cells treated with palmitic acid (PA) and miR-29a, along with luciferase assays, were performed to confirm MAVS pathway interactions.
Main Results:
- Overexpression of miR-29a in mice on a WD significantly reduced liver injury markers, weight gain, and liver weight.
- miR-29a attenuated hepatic fibrosis, oxidative stress, misfolded protein aggregates, and mt-dsRNA release.
- miR-29a inhibited the mitochondrial antiviral-signaling protein (MAVS) pathway, decreasing MAVS expression and mt-dsRNA/superoxide release in HepG2 cells.
Conclusions:
- MicroRNA-29a demonstrates significant therapeutic potential for treating non-alcoholic fatty liver disease (NAFLD) and liver steatofibrosis.
- miR-29a exerts its protective effects by inhibiting the MAVS signaling pathway, thereby reducing inflammation and oxidative stress.
- Targeting miR-29a represents a promising strategy for developing novel treatments for NAFLD.
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