Simvastatin augments activation of liver regeneration through attenuating transforming growth factor‑β1 induced‑apoptosis in obstructive jaundice rats

Abstract

Obstructive jaundice, owing to biliary obstruction, has been illustrated to trigger various biochemical, histological and immunological changes, leading to liver damage or even failure. The detailed molecular mechanism of simvastatin (Sim) involvement in liver regeneration during obstructive jaundice progression remains poorly elucidated. In the present study, an acute obstructive jaundice rat model was established by ligation and division of common bile duct, which was used to investigate the effects of Sim as a hepatoprotective treatment. Male Sprague-Dawley rats were randomly divided into four groups: Sham-operated, bile duct ligation (BDL) plus saline treatment [0.02 mg/kg/d, intraperitoneally (i.p.)], BDL plus low-dose Sim treatment (0.02 mg/kg, i.p.) and BDL plus high-dose Sim treatment (0.2 mg/kg, i.p.). During this experiment, the BDL+normal saline (NS) group demonstrated increased levels of transforming growth factor-β1 (TGF-β1) expression. Furthermore, Sim-treated animals demonstrated significantly downregulated TGF-β1 expression and improved liver function vs. the BDL+NS group, indicating a TGF-β1 antagonizing function. Additionally, Sim increased hepatocyte DNA synthesis in BDL rats compared to both the BDL+NS and Sham group. Apoptosis was increased in BDL+NS compared to the Sham group, and Sim markedly reduced hepatocyte apoptosis in the BDL group. Moreover, analysis of TGF-β1 signaling pathways demonstrated that there was an increased hepatic TGF-β1 and Smad3 expression in the BDL group, which was attenuated in the presence of Sim. In contrast to TGF-β1, Sim induced the activity of the Smad7 (an inhibitor of TGF-β1 signaling) mRNA and Smad7 protein expression. Sim displays hepatoprotective effects in liver cells via the upregulation of Smad7 expression and impaired TGF-β signaling. Furthermore, the observations of the present study may provide evidence on the mechanism behind Sim blunting TGF-β1 signaling, which is used to ameliorate the complication of liver damage and reduce the mortality rates associated with obstructive jaundice.

Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice

“…In the current study, we observed increased TGFβ1 expression localized primarily to hepatocyte populations due to its co-localization with CK8, supporting findings from our previous work demonstrating TGFβ1 co-localization> with albumin during AOM-induced liver failure [12]. Possible consequences of TGFβ1 signaling in hepatocytes may range from induction of apoptotic pathways [31] to the inhibition of hepatocyte proliferation and liver regeneration [29]. In the current study, we have demonstrated that anti-TGFβ1 treatment had similar liver pathology after injection of AOM compared to IgG1 control mice, but had protective effects on the neurological complications associated with acute liver failure.…”

Dexmedetomidine activates the PI3K/Akt pathway to inhibit hepatocyte apoptosis in rats with obstructive jaundice

“…However, the specific mechanism of hepatic injury caused by OJ remains not fully elucidated. An abnormal increase in hepatocyte apoptosis is currently considered to be the pathogenesis of hepatic atrophy caused by OJ (4,5). It has been reported that, due to endotoxin stimulation during OJ, Kupffer cells secrete a large number of inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which induce hepatocyte apoptosis (6,7).…”

The roles of signaling pathways in liver repair and regeneration

“…Furthermore, simvastatin has liver regeneration capability during obstructive jaundice progression and exerts hepatoprotective effects on liver cells via upregulation of Smad7 expression and impaired TGF-β signaling. The expression of hepatic TGF-β1 and Smad3 are augmented during bile duct ligation (Fang et al, 2017). Besides, bone morphogenetic protein (BMP)-9, a member of TGF-β superfamily is constitutively produced in the hepatocytes.…”

“…Following ligand binding with cell surface receptors, Smads are phosphorylated then they associate with Smad4 and translocate into the nucleus to regulate the expression of the target gene. In contrast, Smad signaling is negatively regulated by Smad7 (Fang, He, & Luan, 2017). The studies have revealed that TGF-β is implicated in many kinds of CLD.…”