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Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.
- Source :
-
PLoS biology [PLoS Biol] 2022 Jan 21; Vol. 20 (1), pp. e3001522. Date of Electronic Publication: 2022 Jan 21 (Print Publication: 2022). - Publication Year :
- 2022
-
Abstract
- Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Aging
Animals
Gene Expression Regulation
Gene Knock-In Techniques
Hep G2 Cells
Humans
Lipid Metabolism physiology
Mice
Non-alcoholic Fatty Liver Disease metabolism
PPAR gamma genetics
PPAR gamma metabolism
rab GTP-Binding Proteins genetics
AMP-Activated Protein Kinases metabolism
GTPase-Activating Proteins metabolism
Non-alcoholic Fatty Liver Disease pathology
rab GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1545-7885
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PLoS biology
- Publication Type :
- Academic Journal
- Accession number :
- 35061665
- Full Text :
- https://doi.org/10.1371/journal.pbio.3001522