title: Differentiated embryo chondrocyte 1 (DEC1) is a novel negative regulator of hepatic fibroblast growth factor 21 (FGF21) in aging mice.
abstract: Human differentiated embryo chondrocyte expressed gene 1 (DEC1) is frequently used as a marker of senescence in vivo. Fibroblast growth factor 21 (FGF21), a novel endocrine-like member of the FGF superfamily, is highly expressed in the liver, and FGF21-transgenic mice have extended lifespans. Thus, we hypothesized that FGF21 may play a role in the DEC1-mediated aging process. In this study, DEC1 knockout (KO) mice were used to characterize the mechanism by which FGF21 protects mice from aging. Aging is strongly diminished in DEC1 KO mice, which is reflected by decreased lipid levels and oxidative stress, leading to an amelioration of liver function and structure. The expression of FGF21 decreased with aging in wild-type (WT) mice, whereas ATF4, Phospho-ERK and Phospho-p38 expression was maintained and was accompanied by a compensatory rise of FGF21 mRNA and protein expression in DEC1 KO mice. Over-expression of DEC1 markedly abolished the hepatic expression of FGF21, and siRNA-mediated inhibition of endogenous DEC1 increased the expression of FGF21. DEC1 further diminished the expression of ATF4 in HepG2 cells over-expressing DEC1. The induction of FGF21 and ATF4 at the mRNA and protein levels during the course of aging supports the view that DEC1 KO mice are able to restore the age-related imbalance of metabolism. Collectively, the data obtained in this study suggest that DEC1 is a novel negative regulator of hepatic FGF21 expression.
authors.affiliation: Department of Anesthesiology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan. Electronic address: bhawal.ujjal.kumar@nihon-u.ac.jp.
authors.forename: Ujjal K
authors.initials: UK
authors.lastname: Bhawal
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005346:Fibroblast Growth Factors; D018398:Homeodomain Proteins; C491539:Bhlhe40 protein, mouse; C476387:Fgf22 protein, mouse
keywords: Aging; DEC1; FGF21; Hepatic homeostasis; Liver