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Purpose: Growth hormone (GH) controls liver metabolism through the transcription factor signal transducer and activator of transcription 5 (STAT5). However, it remains to be fully understood to what extent other GH/STAT5 target tissues contribute to lipid and glucose metabolism. This question was now addressed in muscle-specific STAT5 knockout (STAT5 MKO) mice model., Methods: Changes in lipid and glucose metabolism were investigated at physiological and molecular levels in muscle and liver tissues of STAT5 MKO mice under normal diet or high-fat diet (HFD) conditions., Results: STAT5 MKO mice exhibited an increased intramyocellular lipid (IMCL) accumulation in the quadriceps in HFD group. Decreased lipolytic hormone-sensitive lipase transcript levels may contribute to the increased IMCL accumulation in STAT5 MKO mice. STAT5 MKO induced hepatic lipid accumulation without deregulated STAT5 signaling. The upregulation of lipoprotein lipase and Cd36 mRNA levels, an increased trend of very low-density lipoprotein receptor mRNA levels, and elevated circulating concentrations of free fatty acid, triglyceride, and total cholesterol support the increase in hepatic lipid accumulation., Conclusions: STAT5 MKO in conjunction with a HFD deregulated both lipid and glucose metabolism in skeletal muscle, and this deregulation induced hepatic fat accumulation via increased circulating glucose, FFA, and TG concentrations. Our study emphasizes that muscle-specific STAT5 signaling is important for balancing lipid and glucose metabolism in peripheral tissues, including muscle and liver and that the deregulation of local STAT5 signaling augments HFD-induced lipid accumulation in both muscle and liver.

Signal transducers and activators of transcription 5 (STAT5) mediates growth hormone signals, which may control hepatic cholesterol uptake and bile acid metabolism. Deregulation of liver cholesterol homeostasis and bile acid metabolism may cause liver damage and cholesterol gallstone development. The purpose of this study was to understand the role of local STAT5 signaling in cholesterol and bile acid metabolism using liver-specific STAT5 knock-out (STAT5 LKO) mice on a normal diet and a cholesterol- and bile acid-containing lithogenic diet. STAT5 LKO mice showed significant down-regulation of STAT5 and insulin-like growth factor-1 genes. STAT5 gene deletion had a minor effect on cholesterol metabolism, as evidenced by a minor change in circulating cholesterol levels and no changes in expression of hepatic low-density lipoprotein receptor and cholesterol synthesis genes in STAT5 LKO mice. In contrast, bile acid synthesis and uptake genes were profoundly down-regulated and bile acid detoxification genes were up-regulated in STAT5 LKO mice. In STAT5 fl/fl mice, a lithogenic diet induced liver damage, as evidenced by moderate increases in liver ballooning, inflammation and fibrosis. However, STAT5 deletion ameliorated the degree of liver damage induced by the lithogenic diet. In STAT5 LKO mice, a lithogenic diet did not alter the incidence or severity of cholesterol gallstones. In conclusion, local STAT5 signaling does not have a significant role in cholesterol metabolism. In contrast, hepatic STAT5 signaling has significant roles in regulating transcription of genes for synthesis, transport and detoxification of bile acids, but it has only a minor role in bile acid metabolism., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Growth hormone (GH) signal is mediated by signal transducer and activator of transcription 5 (STAT5), which controls hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is clinically associated with a deficiency in GH. This study was performed to understand the role of local STAT5 signaling on hepatic lipid and glucose metabolism utilizing liver-specific STAT5 gene deletion (STAT5 LKO) mice under both normal diet and high-fat diet (HFD) feeding conditions. STAT5 LKO induced hepatic steatosis under HFD feeding, while this change was not observed in mice on normal diet. STAT5 LKO caused hyperglycemia, hyperinsulinemia, hyperleptinemia and elevated free fatty acid and cholesterol concentrations under HFD feeding but induced only hyperglycemia on normal diet. At the molecular level, STAT5 LKO up-regulated the expression of genes involved in lipid uptake (CD36), very low-density lipoprotein receptor (VLDLR), lipogenic stearoyl-CoA desaturase and adipogenic peroxisome proliferator-activated receptor gamma, in both diet groups. In response to HFD feeding, further increases in CD36 and VLDLR expression were found in STAT5 LKO mice. In conclusion, our study suggests that low STAT5 signaling on normal diet predisposes STAT5 LKO mice to early development of fatty liver by hyperglycemia and activation of lipid uptake and adipogenesis. A deficiency in STAT5 signaling under HFD feeding deregulates hepatic and body glucose and lipid metabolism, leading to the development of hepatic steatosis. Our study indicates that low STAT5 signaling, due to low GH secretion, may increase a chance for NAFLD development in elderly people., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Signal transducers and activators of transcription 5 (STAT5) mediates growth hormone signals, which may control hepatic cholesterol uptake and bile acid metabolism. Deregulation of liver cholesterol homeostasis and bile acid metabolism may cause liver damage and cholesterol gallstone development. The purpose of this study was to understand the role of local STAT5 signaling in cholesterol and bile acid metabolism using liver-specific STAT5 knock-out (STAT5 LKO) mice on a normal diet and a cholesterol- and bile acid-containing lithogenic diet. STAT5 LKO mice showed significant down-regulation of STAT5 and insulin-like growth factor-1 genes. STAT5 gene deletion had a minor effect on cholesterol metabolism, as evidenced by a minor change in circulating cholesterol levels and no changes in expression of hepatic low-density lipoprotein receptor and cholesterol synthesis genes in STAT5 LKO mice. In contrast, bile acid synthesis and uptake genes were profoundly down-regulated and bile acid detoxification genes were up-regulated in STAT5 LKO mice. In STAT5 fl/fl mice, a lithogenic diet induced liver damage, as evidenced by moderate increases in liver ballooning, inflammation and fibrosis. However, STAT5 deletion ameliorated the degree of liver damage induced by the lithogenic diet. In STAT5 LKO mice, a lithogenic diet did not alter the incidence or severity of cholesterol gallstones. In conclusion, local STAT5 signaling does not have a significant role in cholesterol metabolism. In contrast, hepatic STAT5 signaling has significant roles in regulating transcription of genes for synthesis, transport and detoxification of bile acids, but it has only a minor role in bile acid metabolism. [ABSTRACT FROM AUTHOR]