Succinate induces hepatic fibrogenesis by promoting activation, proliferation, and migration, and inhibiting apoptosis of hepatic stellate cells

Abstract

Liver fibrosis is a progressive pathological process that accompanies wound healing; however, therapeutics for reversing hepatic fibrosis are unavailable. Activation of hepatic stellate cells (HSCs) play a critical role in liver fibrosis. Recent reports showed that succinate and its receptor, G-protein coupled receptor 91 (GPR91), act as signaling molecules during the activation of HSCs. However, the role of succinate in proliferation, apoptosis, and migration of HSCs has not been studied. In this study, we determined whether succinate regulates proliferation, apoptosis, and migration of HSCs and induces liver fibrosis in a mouse model.Succinate treatment not only induced activation of HSCs, but also increased the proliferation and migration of LX-2 HSCs and inhibited apoptosis. To investigate whether succinate causes hepatic fibrosis, 100 mg/kg succinate or control PBS was administered by intraperitoneal injection to mice once a day for four weeks. There were significant molecular changes such as increased α-SMA and collagen type 1 production and increased production of inflammatory cytokines such as IL-6 and TNF-α, but not TGF-β, in the succinate-treated group compared to the control group. However, no morphological changes were observed in Masson's trichrome staining. In conclusion, the present study demonstrated that succinate induces activation, proliferation, and migration of HSCs and attenuates apoptosis in LX-2 HSCs. Therefore, inhibition of succinate accumulation may be an effective method for reversing liver fibrosis by controlling HSC survival and growth.