mTOR Overactivation in Mesenchymal cells Aggravates CCl4- Induced liver Fibrosis.
Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl4, oil or CCl4+ rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl4- induced liver fibrosis and the rapamycin prevent its occurance.
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Lanlan
L
Shan
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Yan
Y
Ding
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
You
Y
Fu
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Ling
L
Zhou
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Xiaoying
X
Dong
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Shunzhi
S
Chen
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Hongyuan
H
Wu
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Wenqing
W
Nai
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Hang
H
Zheng
Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
Wanfu
W
Xu
Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Xiaochun
X
Bai
Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Chunhong
C
Jia
Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Meng
M
Dai
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004195:Disease Models, Animal; D017353:Gene Deletion; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D002251:Carbon Tetrachloride; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus