The effect of the red wine polyphenol resveratrol on a rat model of biliary obstructed cholestasis: involvement of anti-apoptotic signalling, mitochondrial biogenesis and the induction of autophagy

Abstract

Mitochondria are known to be involved in cholestatic liver injury. The potential protective effect of resveratrol in cholestatic liver injury and the possible roles of autophagy and apoptosis induction in this process are not yet clear. The aim of this study is to determine whether resveratrol administration after bile duct ligation can reduce cholestasis-induced liver injury through modulating apoptosis, mitochondrial biogenesis and autophagy. A rat model of cholestasis was established by bile duct ligation (BDL) and compared with a sham group receiving laparotomy without BDL, with resveratrol or control treatments following BDL. The expression of proteins involved in the apoptotic and autophagic pathways were analyzed by western blotting. Apoptosis was examined by TUNEL staining. In the resveratrol/BDL group LC3-II upregulation persisted for 1-7 days, Bax was downregulated and catalase was upregulated at 3-7 days after resveratrol treatment. The decline in mitochondrial DNA copy number was reversed at 3-7 days. Caspase 3 expression was significantly downregulated at 3-7 days in the resveratrol group. TUNEL staining showed significant numbers of apoptotic liver cells appeared in livers 3-7 days after BDL and that was decreased by resveratrol treatment. Our results indicate that early resveratrol treatment reverses impaired liver function within hours of BDL.

Decreasing Mitochondrial Fission Prevents Cholestatic Liver Injury

“…It has been shown that cholestasis is associated with hepatic mitochondrial dysfunction, which includes loss of membrane potential and ATP production, reduced fatty acid oxidation, impaired respiratory complex activities, and decreased respiration, (6,7). In addition, a decrease in mitochondrial biogenesis was reported in cholestasis along with impairment of autophagy (45). Mitochondrial deformation suggestive of increased division and swelling was reported in cholestatic livers decades ago (21).…”

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

“…The forward and reverse primers for mtDNA, which are complementary to the sequence of the mitochondrial COX1 gene, were 5'-GGAGCAGTATTCGCCATCAT-3' and 5'-CGGCCGTAAGTGAGATGAAT-3', respectively. The PCR was performed in an IQ5 Real-Time PCR System (BioRad Co, USA) as previously described [14] . The threshold cycle number (Ct) values of the β-actin gene and the mitochondrial ND1 gene were determined for each individual quantitative PCR run.…”

“…An ANIT dosing regimen was adopted as described previously [23] . Because of variable resveratrol dosage schemes and its reported poor oral bioavailability, we administered resveratrol at doses of 15 and 30 mg·kg -1 ·d -1 via intraperitoneal injections, which were reported to alleviate rat extrahepatic cholestasis and oxidative damage [12,14] .…”

“…Recently, it was found that resveratrol improved cholestatic liver injury by decreasing fibrosis and promoting hepatocyte regeneration [12] , decreasing oxidative damage [13] , and modulating apoptosis, mitochondrial biogenesis and autophagy [14] . The current evidence for the protective effect of resveratrol on cholestasis was mainly obtained from studies using bile duct ligation (an extrahepatic model) in animals.…”

Bone marrow mononuclear cell transplantation improves mitochondrial bioenergetics in the liver of cholestatic rats

“…Liver fibrosis is characterized by fibrogenesis dysregulation as a chronic inflammatory process result leading to extracellular matrix components accumulation and hepatic architecture disruption [8,26,23,52,36]. n retention in the liver, process called cholestasis, which is responsible for severe liver biochemical and structural changes [21,10,32]. From the biochemical point of view, the overall mitochondrial function is impaired, resulting in a marked metabolic disorder, characterized by reduced carbohydrate and fatty acid oxidation [3].…”