Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8336481 | The Journal of Nutritional Biochemistry | 2017 | 37 Pages |
Abstract
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.
Keywords
β-muricholic acidFXRABCC2ABCB4DCAOROα-muricholic acidSTAT5SCARB1ABCG5ABCG8cytochrome P450, family 7, subfamily a, polypeptide 1Lithogenic dietCYP8B1lipoprotein receptor-related protein 1TCDCASULT2A1CYP7B1TDCAGCDCATβMCACyp2b10ABCB11CDCACYP7A1TCAHMGCRLRP1LDLRGCAIGF-13-Hydroxy-3-Methylglutaryl-coenzyme A reductasefarnesoid X receptorH&ELiver DamageChenodeoxycholic acidDeoxycholic acidTaurodeoxycholic acidTaurocholic acidCholic acidGlycochenodeoxycholic acidglycocholic acidBile acidsinsulin-like growth factor-1triacylglycerolGallstonessignal transducer and activator of transcription 5Hematoxylin and EosinGrowth hormonepolymerase chain reactionPCRLow-density lipoprotein receptor
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Authors
Myunggi Baik, Jangseon Kim, Min Yu Piao, Hyeok Joong Kang, Seung Ju Park, Sang Weon Na, Sung-Hoon Ahn, Jae-Hyuk Lee,