Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation.

BACKGROUND: The activation of hepatic stellate cells (HSCs) is the key step in the pathogenesis of liver fibrosis, which directly leads to fibrotic pathological changes in the hepatic tissue. Mitochondrial stress exacerbates inflammatory diseases by inducing pathogenic shifts in normal cells. However, the role of mitochondrial stress in HSC activation remains to be elucidated.  METHODS: We analyzed the effect of mitochondrial stress on HSC activation. An in vivo hepatic fibrosis model was established by intraperitoneal injection of 40% carbon tetrachloride (CCl4) for 12 weeks. Additionally, using in vitro approach, HSC-T6 cells were treated with 10 ng/mL platelet-derived growth factor-BB (PDGF-BB) for 24 h. RESULTS: Transcriptional activator 4 (ATF4) is highly expressed in fibrotic liver tissue samples and activated HSCs. We found that AAV8-shRNA-Atf4 alleviated liver fibrosis in rats. ATF4 promoted the activation of HSCs, which was induced by mitochondrial stress. The mechanisms involved ATF4 binding to a specific region of the tribble homologue 3 (TRIB3) promoter. Further, TRIB3 promoted HSCs activation mediated by mitochondrial stress. CONCLUSIONS: ATF4 induces mitochondrial stress by upregulating TRIB3, leading to the activation of HSCs. Therefore, the inhibition of ATF4 during mitochondrial stress may be a promising therapeutic target for liver fibrosis.

TIM­3 inhibits PDGF­BB­induced atherogenic responses in human artery vascular smooth muscle cells.

Increasing evidence suggests that T­cell immunoglobulin and mucin domain 3 (TIM­3) displays anti­atherosclerotic effects, but its role in vascular smooth muscle cells (VSMCs) has not been reported. The present study aimed to investigate the function of TIM­3 and its roles in human artery VSMCs (HASMCs). A protein array was used to investigate the TIM­3 protein expression profile, which indicated that TIM­3 expression was increased in the serum of patients with lower extremity arteriosclerosis obliterans disease (LEAOD) compared with healthy individuals. Immunohistochemistry and western blotting of arterial tissue further revealed that TIM­3 expression was increased in LEAOD artery tissue compared with normal artery tissue. Additionally, platelet­derived growth factor­BB (PDGF­BB) displayed a positive correlation with TIM­3 expression in HASMCs. TIM­3 decreased the migration and proliferation of PDGF­BB­induced HASMCs, and anti­TIM­3 blocked the effects of TIM­3. The effect of TIM­3 on the proliferation and migration of HASMCs was further investigated using LV­TIM­3­transduced cells. The results revealed that TIM­3 also inhibited PDGF­BB­induced expression of the inflammatory factors interleukin­6 and tumor necrosis factor­α by suppressing NF­κB activation. In summary, the present study revealed that TIM­3 displayed a regulatory role during the PDGF­BB­induced inflammatory reaction in HASMCs, which indicated that TIM­3 may display anti­atherosclerotic effects.