Visfatin exacerbates hepatic inflammation and fibrosis in a methionine‐choline‐deficient diet mouse model

Abstract

Background and Aim Non‐alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non‐alcoholic steatohepatitis, which is characterized by hepatic inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Visfatin, an adipocytokine, was reported to induce pro‐inflammatory cytokines and can be associated with liver fibrosis. We investigated the role of visfatin on hepatic inflammation and fibrosis in a methionine‐choline‐deficient (MCD)‐diet‐induced steatohepatitis mouse model. Methods Eight‐week‐old male C57BL/6 J mice were randomly assigned into one of three groups: (1) saline‐injected control diet group; (2) saline‐injected MCD diet group; and (3) visfatin‐injected MCD diet group (n = 8 per group). Mice were administered intravenous saline or 10 μg/kg of recombinant murine visfatin for 2 weeks. Histologic assessment of liver and biochemical and molecular measurements of endoplasmic reticulum (ER) stress, reactive oxidative stress (ROS), inflammation, and fibrosis were performed in livers from these animals. Results Visfatin injection aggravated hepatic steatosis and increased plasma alanine aminotransferase and aspartate aminotransferase concentrations. Visfatin increased inflammatory cell infiltration (as indicated by F4/80, CD68, ly6G, and CD3 mRNA expression) and expression of chemokines in the liver. Visfatin also increased the expression of pro‐inflammatory cytokines (IL‐1β, TNF‐α, and IL‐6) and activated fibrosis markers (CTGF, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin) in liver. Livers of visfatin‐injected mice showed upregulation of ER stress and ROS and activation of JNK signaling. Conclusions These results suggest that visfatin aggravates hepatic inflammation together with induction of ER and oxidative stress and exacerbates fibrosis in an MCD‐diet‐fed mouse model of NAFLD.

CCL23 in Balancing the Act of Endoplasmic Reticulum Stress and Antitumor Immunity in Hepatocellular Carcinoma

“…A study in type 2 diabetic mouse model showed that inhibiting chemokine receptor 2 (receptor for CCL2) improves hepatic steatosis by reducing ER stress and inflammation ( 69 ). Additionally, visfatin-induced hepatic inflammation in a mouse model of methionine-choline-deficient diet showed increased CXCL2, CXCL8, and MCP-1 associated with ER stress upregulation ( 70 ). On the other hand, in a breast cancer study, tunicamycin-activated ER stress increases the endogenous level of CCL5 mRNA and protein and prevents MCF-7 cells migration ( 71 ).…”

Cytoskeleton alterations in non-alcoholic fatty liver disease

“…A distinct study also detected vimentin up-regulation in hepatocytes of MCD diet-fed mouse model to induce NASH phenotype 42 . Similarly, vimentin was also up-regulated in a NAFLD mouse model (MCD diet-fed-mice) treated with a pro-inflammatory fibrosis inducer 22 . Vimentin up-regulation and cleavage could also be detected in the HepG2 hepatocyte cell line and also in hepatocytes treated with palmitic acid 43 .…”

“…2). For instance, fibronectin, another extracellular matrix component, was also up-regulated in livers of NAFLD mice 22 . Excessive deposition of extracellular matrix components induces fibrosis, disrupts the normal architecture of the liver and results in hepatic dysfunction 23 .…”

Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

“…And ER stress is associated with ROS level. A research found that both ER stress and ROS levels were increased in visfatin-treated livers and accompanied by hepatic damage [30]. Sharma et al found that in hepatic stellate cells, ER stress and oxidative stress were induced by sorafenib to cause hepatic cell death, giving an evidence that ER stress was consistent with oxidative stress to cause liver damage together [31].…”

“…Previous studies showed that the production of ROS was associated with the activation of the JNK signaling pathway. Heo et al found the upregulation of ER stress and the production of ROS as well as the activation of the JNK signaling pathway in the livers of visfatin-administered mice [30]. Another study demonstrated that hyperuricemia induced the activation of the JNK signaling pathway and caused elevated levels of ROS, indicating that the production of ROS may occur through the JNK signaling pathway [73].…”