Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation
Sunmi Seok, … , Byron Kemper, Jongsook Kim Kemper
Sunmi Seok, … , Byron Kemper, Jongsook Kim Kemper
Published June 18, 2018
Citation Information: J Clin Invest. 2018;128(7):3144-3159. https://doi.org/10.1172/JCI97736.
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Research Article Cell biology Metabolism

Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation

Abstract

Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation–promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.

Authors

Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper

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Figure 6

Liver-specific downregulation of JMJD3 leads to impaired β-oxidation and fatty liver symptoms.

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Liver-specific downregulation of JMJD3 leads to impaired β-oxidation and...
(A–J) JMJD3-floxed mice were infected with AAV-TBG-Cre or control AAV-TBG-GFP for 3 months. (A) Experimental outline. Blot shows protein levels of JMJD3 in liver, BAT, subcutaneous WAT (sWAT), and gonadal WAT (gWAT) in pooled samples from 6 mice. (B) Body weight (BW) and image of adipose and liver tissues. rWAT, retroperitoneal WAT. (C) Liver sections were stained with H&E and oil red O. Scale bar: 100 μm. (D) Hepatic TG and serum NEFA levels. (E) Blood glucose levels were determined by glucose tolerance test (GTT). (F) mRNA levels of the indicated hepatic genes. (G) Ratios of H3K27-me3 to total histone H3 at the indicated genes were determined by ChIP. (H) Palmitate oxidation rates in liver extracts. (I) Levels of liver acylcarnitines and serum β-hydroxybutyrate. (J) O2 consumption and CO2 production rates were measured by indirect calorimetry. (K and L) Primary mouse hepatocytes were infected with lentivirus expressing JMJD3 shRNA or control shRNA, and (K) the palmitate oxidation rate and glucose production were determined. (L) p-AKT and AKT levels were measured by IB in hepatocytes treated with insulin for 10 minutes. n = 6–8 mice/group (B and D–J); n = 3 independent assays (K). Data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test. The P values in (J) were determined by the Student’s t test for the average values measured over the times indicated.