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RBM15 impairs Hepatic Mitochondria and β-Oxidation through m6A-dependent degradation of MCM3 mRNA
Kai Chen1, Yi Xiang1, Daqing Deng1
1Department of Cardiovascular Medicine Six Wards (Cardiovascular and Metabolic Diseases), Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, China.
Abstract:
Diabesity, defined as obesity accompanied by Type 2 diabetes mellitus, is characterized by metabolic dysfunction and mitochondrial impairment. Here, we investigate the role of N6-methyladenosine (m6A)-mediated RNA regulation in regulating hepatic mitochondrial function and fatty acid β-oxidation during diabesity progression. Diabesity was modeled in male C57BLKS/J db/db mice, with db/m lean mice as controls; in vitro models were established using primary hepatocytes isolated from male C57BL/6J mice exposed to high glucose and palmitate. Our results showed that MCM3 was significantly downregulated in diabesity models. MCM3 overexpression improved hepatic mitochondrial function and fatty acid β-oxidation. Mechanistically, MCM3 increased NRF2 in hepatocytes by competitive combination with KEAP1. In addition, RBM15 overexpression accelerated m6A-YTHDF2-mediated MCM3 mRNA decay. As expected, MCM3 knockdown negated the metabolic benefits of RBM15 knockdown. In conclusion, m6A-dependent MCM3 downregulation by RBM15/YTHDF2 impaired hepatic mitochondrial function and fatty acid β-oxidation in diabesity by reducing NRF2.
Insights
Diabesity impairs liver function by downregulating MCM3, a key protein for mitochondrial health and fatty acid breakdown. This RNA regulation impacts metabolic dysfunction in obesity and Type 2 diabetes.
Area of Science:
- Metabolic research
- Molecular biology
- Epigenetics
Background:
- Diabesity (obesity with Type 2 diabetes) involves metabolic dysfunction and impaired liver mitochondria.
- N6-methyladenosine (m6A)-mediated RNA regulation is implicated in metabolic diseases.
Purpose of the Study:
- To investigate the role of m6A RNA regulation in hepatic mitochondrial function and fatty acid oxidation during diabesity.
- To identify key molecular players involved in this process.
Main Methods:
- Diabesity was modeled using C57BLKS/J db/db mice and in vitro hepatocyte models with high glucose and palmitate.
- MCM3 expression, mitochondrial function, and fatty acid β-oxidation were assessed.
- m6A regulators (RBM15, YTHDF2) and their impact on MCM3 mRNA stability were analyzed.
- NRF2 pathway activation was examined.
Main Results:
- MCM3 was significantly downregulated in diabesity models, correlating with impaired mitochondrial function and fatty acid β-oxidation.
- MCM3 overexpression ameliorated these metabolic deficits by increasing NRF2 levels via KEAP1 interaction.
- RBM15/YTHDF2 pathway accelerated MCM3 mRNA decay, and MCM3 knockdown reversed RBM15 knockdown's benefits.
Conclusions:
- m6A-dependent downregulation of MCM3 by RBM15/YTHDF2 impairs hepatic mitochondrial function and fatty acid β-oxidation in diabesity.
- This downregulation contributes to metabolic dysfunction by reducing NRF2 levels.
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