Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms.
Insulin sensitivity in liver is characterized by the ability of insulin to efficiently inhibit glucose production and fatty acid oxidation as well as promote de novo lipid biosynthesis. Specific dysregulation of glucose and lipid metabolism in liver is sufficient to cause insulin resistance and type 2 diabetes; this is seen by a selective inability of insulin to suppress glucose production while remaining insulin-sensitive to de novo lipid biosynthesis. We have previously shown that the transcription factor Yin Yang 1 (YY1) controls diabetic-linked glucose and lipid metabolism gene sets in skeletal muscle, but whether liver YY1-targeted metabolic genes impact a diabetic phenotype is unknown. Here we show that decreased genetic dosage of YY1 in liver causes insulin resistance, hepatic lipid accumulation, and dyslipidemia. Indeed, YY1 liver-specific heterozygous mice exhibit blunted activation of hepatic insulin signaling in response to insulin. Mechanistically, YY1, through direct recruitment to promoters, functions as a suppressor of genes encoding for metabolic enzymes of the gluconeogenic and lipogenic pathways and as an activator of genes linked to fatty acid oxidation. These counterregulatory transcriptional activities make targeting hepatic YY1 an attractive approach for treating insulin-resistant diabetes.
Department of Cancer Biology (F.V., S.M.B., J.T.C., J.A.H., H.C., P.P.), Dana-Farber Cancer Institute, and Department of Cell Biology (F.V., S.M.B., J.T.C., J.A.H., H.C., P.P.), Harvard Medical School, Boston, Massachusetts 02115.
Francisco
F
Verdeguer
Sharon M
SM
Blättler
John T
JT
Cunningham
Jessica A
JA
Hall
Helen
H
Chim
Pere
P
Puigserver
D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D050171:Dyslipidemias / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006579:Heterozygote; D006706:Homeostasis; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D050986:YY1 Transcription Factor / Q000172:deficiency / Q000235:genetics*
D005227:Fatty Acids; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse