HDAC5 Inhibits Hepatic Lipogenic Genes Expression by Attenuating the Transcriptional Activity of Liver X Receptor.
OBJECTIVE
Liver X receptor (LXR), a member of the nuclear receptor superfamily, is known to induce the expression of SREBP-1c and ChREBP, two master regulators of hepatic lipogenesis. Histone deacyetylases (HDACs) have been shown to play critical roles in glucose and lipids metabolism. However, the exact role of HDAC5 in lipogenesis remains elusive.


METHODS
mRNA and protein levels of HDAC5 were analyzed by quantitative real-time PCR and Western blots in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. HDAC5 was overexpressed or depleted in HepG2 cells, followed by analysis of cellular triglycerides contents. Quantitative real-time PCR was used to detect the expression levels of lipogenic genes. Luciferase reporter assay was used to determine the regulation of HDAC on the transcriptional activity of LXR. Co-immunoprecipitation experiment was used to determine the interaction between HDAC5 and LXR.


RESULTS
We found that mRNA and protein expression levels of hepatic HDAC5 were reduced in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. In vitro studies further demonstrated that knockdown of HDAC5 promoted cellular triglycerides accumulation, accompanied with up-regulation of lipogenic genes. At the molecular level, HDAC5 was shown to interact with LXR, thereby attenuating its transcriptional activity.


CONCLUSIONS
Overall, our data suggest that hepatic HDAC5 is an important regulator of lipogenesis.
Department of Endocrinology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Hai-Yan
HY
Jia
Quan-Zhong
QZ
Li
Li-Fang
LF
Lv
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D054411:Receptors, Leptin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; C515447:leptin receptor, mouse; D008156:Luciferases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D005947:Glucose