Deletion of liver-specific STAT5 gene alters the expression of bile acid metabolism genes and reduces liver damage in lithogenic diet-fed mice.
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.
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea; Institute of Green Bio Science Technology, Gangwon-do, Pyeungchang-gun 232-916, Republic of Korea. Electronic address: mgbaik@snu.ac.kr.
Myunggi
M
Baik
Bioneer Corporation, 8-11 Munpyengseoro, Daedeok-gu, Daejeon 306-220, Republic of Korea.
Jangseon
J
Kim
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea.
Min Yu
MY
Piao
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea.
Hyeok Joong
HJ
Kang
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea.
Seung Ju
SJ
Park
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea.
Sang Weon
SW
Na
College of Pharmacy, Kangwon National University, Chuncheo, Republic of Korea.
Sung-Hoon
SH
Ahn
Department of Pathology, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea.
Jae-Hyuk
JH
Lee
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004032:Diet; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D014280:Triglycerides; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
Bile acids; Gallstones; Growth hormone; Lithogenic diet; Liver damage; STAT5