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Hepatic lipid accumulation induces alterations of histone H3 lysine 4 and 9 trimethylation that modulate hepatic triglyceride synthesis in mouse primary hepatocytes
Author(s) -
Jun Heejin,
Kim Jinyoung,
Lee Ji Hae,
Jia Yaoyao,
Lee SungJoon
Publication year - 2011
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.25.1_supplement.597.3
Liver steatosis, characterized with excessive hepatic lipid accumulation, is commonly found in the patients with hyperlipidemia. Aberrant histone methylation is associated with the hyperlipidemia by altering the transcription of genes in energy metabolism with epigenetic regulation. Therefore, we investigated genome‐wide changes of histone H3 lysine (K) 4 and 9 trimethylation (me3) with chromatin immunoprecipitation (ChIP)‐on‐chip and in lipid‐accumulated mouse primary hepatocytes and oligonucleotide microarray analysis in the livers of high‐fat fed human apolipoprotein E2 transgenic mice. The ChIP‐on‐chip and transcriptome analyses showed that the lipid accumulation altered the H3K4me3 and H3K9me3 at global levels and changed the expressions of major histone trimethyltransferases including Suv39h1 , Kdm4b, Kdm5b and Kdm5c . Hepatic lipid accumulation directly induced the gene expression in hepatic triglyceride synthesis and glycolysis, however, reduced the gene expression in fatty acid oxidation. The expressions of the key genes in triglyceride synthesis process, acetyl‐CoA carboxylase (+1.2‐fold), fatty acid synthase (+1.4‐fold), stearoyl‐CoA desaturase (7.7‐fold) and glycerol‐3‐phosphate acyltransferse (1.2‐fold), were significantly elevated. Glucose kinase (+1.3‐fold) and pyruvate kinase (+2.1‐fold) expressions in glycolysis were up‐regulated and the expression of acetyl‐CoA acyltransferase 1A (−1.7‐fold), 3‐hydroxy‐3‐methylglutaryl‐CoA lyase (−1.3‐fold) and cytochrome P450, family 4, subfamily a, polypeptide 14 (−2.5‐fold) in fatty acid β‐ and ω‐oxidation were down‐regulated. In parallel, ChIP‐on‐chip results showed that the transcription of the genes in fatty acid and glucose metabolism were associated with H3K4me3 and H3K9me3 in their promoters. In conclusion, hepatic lipid accumulation affects fatty acid metabolism and glycolysis by regulating H3K4me3 and H3K9me3.