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All‐trans‐retinoic Acid ( at RA) Enhances Mitochondrial Biogenesis in Models of Human Liver
Author(s) -
Tripathy Sasmita,
Foti Robert,
Isoherranen Nina
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.779.9
Subject(s) - mitochondrial biogenesis , nrf1 , retinoic acid , mitochondrion , tfam , biology , microbiology and biotechnology , biochemistry , gene
Recently non‐alcoholic fatty liver disease (NAFLD) has emerged as a disease resulting from mitochondrial dysfunction and defects in mitochondrial biogenesis. While all‐trans‐retinoic acid ( at RA) has been established as a positive regulator of mitochondrial function in skeletal muscle, its role on regulating hepatic mitochondrial biogenesis has not been explored. In the present study, we used lipid loaded human hepatoma (HepG2) cells and human primary hepatocytes as models to examine the role of at RA in regulating hepatic mitochondrial biogenensis. HepG2 cells and human hepatocytes were cultured in the presence or absence of at RA for 24 or 48 hrs, after which, cells were harvested for RNA and protein isolation in order to evaluate gene and protein expression. Treatment with at RA significantly increased mRNA expression of key mitochondrial biogenensis markers such as PGC1α, PGC1β and NRF1. Additionally, at RA treatment increased SDH (a mitochondrial activity marker) protein expression and mitochondrial ATP production in HepG2 cells. Talarozole, an inhibitor of at RA metabolism, significantly increased at RA concentrations and decreased 4‐OH‐ at RA and 4‐oxo‐ at RA concentration in cell media. Additionally, in the presence of talarozole, at RA additively increased mRNA expression of PGC1α, PGC1β and NRF1 and ATP production suggesting that at RA metabolism by CYP26 enzymes limits its effect on mitochondrial biogenesis. Collectively, these results indicate that at RA enhances mitochondrial biogenesis and activity, and CYP26A1 may be a potential therapeutic target for NAFLD. (Funding: NIH R01 GM111772 and GM081569).