Abstract
Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Diet, High-Fat / adverse effects
-
Eating / genetics
-
Eating / physiology
-
Female
-
Gene Expression Regulation
-
Genome-Wide Association Study
-
Hep G2 Cells
-
Histones / metabolism
-
Humans
-
Insulin / metabolism
-
Insulin / pharmacology
-
Insulin Resistance
-
Jumonji Domain-Containing Histone Demethylases / genetics
-
Jumonji Domain-Containing Histone Demethylases / metabolism*
-
Lipogenesis / drug effects
-
Lipogenesis / genetics
-
Lipogenesis / physiology*
-
Lysine / metabolism
-
Male
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Oxidoreductases, N-Demethylating / genetics
-
Oxidoreductases, N-Demethylating / metabolism*
-
Phosphorylation
-
Promoter Regions, Genetic
-
TOR Serine-Threonine Kinases / metabolism*
-
Triglycerides / blood
-
Triglycerides / metabolism
-
Upstream Stimulatory Factors / metabolism
Substances
-
Histones
-
Insulin
-
Triglycerides
-
USF1 protein, human
-
Upstream Stimulatory Factors
-
JMJD1C protein, human
-
JMJD1c protein, mouse
-
Jumonji Domain-Containing Histone Demethylases
-
Oxidoreductases, N-Demethylating
-
MTOR protein, human
-
TOR Serine-Threonine Kinases
-
Lysine