title: Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice.
abstract: FAM3C is a member of the family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia, and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM), and phosphorylated protein kinase B (Akt) and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca2+- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Biomedical Informatics, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Junpei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science & Technology School of Life Science & Technology, Wuhan, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Chen
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Geng
authors.affiliation: Department of Biomedical Informatics, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China yangj@bjmu.edu.cn.
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002147:Calmodulin / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005943:Gluconeogenesis / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C000595843:Calm1 protein, mouse; D002147:Calmodulin; D016207:Cytokines; D004268:DNA-Binding Proteins; C488587:Fam3c protein, mouse; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt