In:
PLOS Biology, Public Library of Science (PLoS), Vol. 20, No. 1 ( 2022-1-21), p. e3001522-
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 TBC1D1 S231A -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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001522
DOI:
10.1371/journal.pbio.3001522.g001
DOI:
10.1371/journal.pbio.3001522.g002
DOI:
10.1371/journal.pbio.3001522.g003
DOI:
10.1371/journal.pbio.3001522.g004
DOI:
10.1371/journal.pbio.3001522.g005
DOI:
10.1371/journal.pbio.3001522.g006
DOI:
10.1371/journal.pbio.3001522.g007
DOI:
10.1371/journal.pbio.3001522.s001
DOI:
10.1371/journal.pbio.3001522.s002
DOI:
10.1371/journal.pbio.3001522.s003
DOI:
10.1371/journal.pbio.3001522.s004
DOI:
10.1371/journal.pbio.3001522.s005
DOI:
10.1371/journal.pbio.3001522.s006
DOI:
10.1371/journal.pbio.3001522.s007
DOI:
10.1371/journal.pbio.3001522.s008
DOI:
10.1371/journal.pbio.3001522.s009
DOI:
10.1371/journal.pbio.3001522.s010
DOI:
10.1371/journal.pbio.3001522.s011
DOI:
10.1371/journal.pbio.3001522.s012
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2126773-X