Berberine protects steatotic donor undergoing liver transplantation via inhibiting endoplasmic reticulum stress-mediated reticulophagy

Abstract

Steatotic livers are more susceptible to ischemia/reperfusion injury, and increase the risk of primary graft non-function after liver transplantation. The protective effects of berberine have been described in various liver pathological models. However, it is unknown if berberine exerts its beneficial action in steatotic donors undergoing liver transplantation. In the present study, male Wistar rats were fed with high-fat diet (HFD) for 12 weeks to induce moderate steatotic liver. Then orthotropic liver transplantation was constructed. Berberine (200 mg/kg/d) was given intragastrically one week before liver transplantation. Thapsigargin (TG) (0.2 mg/kg) was administrated intravenously 24 h before liver transplantation. Liver function, oxidative stress, and inflammatory cytokine were detected by biochemical or histopathological analysis. The morphology of autophagosomes and endoplasmic reticulum (ER) was observed by transmission electron microscopy. The expression of CHOP, BIP, the phosphorylation of PERK, LC3-II/I, Beclin-1, and p62 were determined by Western blot assay. The co-localization of endoplasmic reticulum marker (KDEL) and autophagic protein (LC3B) was analyzed by immunofluorescence microscopy. The level of reticulophagy hallmark (FAM134B) was determined by immunohistochemistry. Compared with HFD + LT group, berberine ameliorated hepatocellular damage, decreased the oxidative stress level and inflammatory cytokine release. Simultaneously, berberine inhibited the expression of both endoplasmic reticulum stress parameters and autophagy-related proteins. Additionally, the co-localization of endoplasmic reticulum marker and LC3B was also reduced in HFD + BBR + LT group. berberine down-regulated the level of FAM134B. TG reversed the beneficial effects of berberine. Our study revealed that berberine exerts protective effects on steatotic livers undergoing transplantation by inhibiting endoplasmic reticulum stress-mediated reticulophagy. Impact statement Berberine is isolated from traditional Chinese medicine plants and has dramatically therapeutic potential against inflammation, diarrhea, and diabetes. But the benefits of BBR on steatotic grafts after liver transplantation remain poorly understood. Our findings might help explain the mechanism of berberine in protecting steatotic livers undergoing transplantation and give advantageous insights that berberine has potential as a suitable candidate for preventing hepatic injury after steatotic liver transplantation by inhibiting ER stress-mediated reticulophagy.

New Insights Into the Role of Autophagy in Liver Surgery in the Setting of Metabolic Syndrome and Related Diseases

“…Furthermore, under these conditions, the pharmacological inhibition of autophagy protected steatotic liver grafts. This study also generated another important result in the setting of transplantation: in steatotic grafts, berberine inhibited autophagy and protected the graft, but the same drug activated autophagy in optimal grafts and decreased liver injury (Lin et al, 2017;Zhang et al, 2019). This observation underscores the very different signaling mechanisms that act in optimal vs. steatotic grafts, despite being subjected to the same surgical maneuvers.…”

“…Very few experimental studies have evaluated the role of autophagy in transplantation of NAFLD grafts (Gracia-Sancho et al, 2013;Zaouali et al, 2013aZaouali et al, ,b, 2017Panisello-Roselló et al, 2017Zhang et al, 2019). To date, reported results differ depending on the experimental model used.…”

Natural products and phytochemical nanoformulations targeting mitochondria in oncotherapy: an updated review on resveratrol

“…For instance, resveratrol can affect the ER to exert its therapeutic impacts [116]. This story is also similar for curcumin [62], berberine [80], emodin [122] and other natural products. So, it is conspicuous that organelles can be considered as potential targets of these natural products.…”

“…The structure of mitochondria is of importance in induction or inhibition of apoptotic cell death [77,78]. Accumulating data demonstrates that mitochondria are the central gateway of the intrinsic pathway of apoptosis [79,80]. This reveals the potential role of mitochondria in the regulation of life and death [81,82].…”

The Protective Effect of Traditional Chinese Medicine on Liver Ischemia-Reperfusion Injury

“…Zhang et al found that berberine (BBR), a compound derived from the traditional Chinese medicine plants, inhibits endoplasmic reticulum stress-mediated phagocytosis in steatotic liver transplantation. It is the first report that addresses the protective function of BBR on steatosis liver transplantation, but the specific mechanism involved still remains unclear [ 23 ]. Besides, saffron ethanol extract can also relieve the endoplasmic reticulum stress and protein ubiquitination induced by liver I/R [ 8 ].…”