An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: Regulation of proinflammatory cytokines and hepatic steatosis in mice

Abstract

Background and Aims The importance of chemokines in alcoholic liver injury has been implicated. The role of chemokine, monocyte chemoattractant protein-1 (MCP-1) elevated in patients with alcoholic liver disease is not yet understood. Here we evaluate the pathophysiological significance of MCP-1 and its receptor CCR2 in alcoholic liver injury. Methods Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1 deficient (KO) mice for 5 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. Results MCP-1 was increased in Kupffer cells as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum ALT, in WT and CCR2KO but not MCP-1KO mice. Alcohol-induced liver steatosis and triglyceride was attenuated in alcohol-fed MCP-1KO but high in CCR2KO compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver pro-inflammatory cytokines TNFα, IL-1β, IL-6, KC/IL-8, ICAM-1 and CD68 was induced in alcohol-fed WT mice but inhibited in MCP-1KO, independent of NFκB activation in Kupffer cells. Oxidative stress, but not CYP2E1, was prevented in chronic alcohol-fed MCP-1KO mice compared to WT. Increased expression of PPARα and PPARγ, was accompanied by nuclear translocation, DNA binding and induction of fatty acid metabolism genes, ACOX and CPT-1, in livers of alcohol-fed MCP-1KO mice compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARα mRNA and PPRE binding in hepatocytes, independent of CCR2. Conclusion Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of pro-inflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism.

Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells

“…Once released, IL-1β has been shown to act in both autocrine and paracrine fashions to increase its own expression (Szabo & Petrasek 2015) as well as the expression of other proinflammatory cytokines, including TNF α (Mandrekar et al 2011), though we did not observe the latter in our studies. IL-1β activates hepatic stellate cells leading to fibrosis (Miura et al 2010) and increases triglyceride accumulation in hepatocytes (Miura et al 2010, Petrasek et al 2012.…”

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

“…It was observed that CYP2E1 is upregulated in NASH associated with type 2 diabetes mellitus and obesity (11,18). It was also shown that binge ethanol exposure upregulates CYP2E1 and increases liver injury in obese rats (46).…”

“…The "second hit" is generally attributed to oxidative stress that triggers lipid peroxidation of hepatocyte membrane (9). This process results in production of proinflammatory cytokines and triggers activation of hepatic stellate cells, which initiate liver fibrosis (10,11). Lipid peroxidation and generation of reactive oxygen species (ROS) can also directly and adversely affect hepatocytes, resulting in necrosis and cell death (12).…”

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

“…10,11 Several reports suggest that chronic inflammation, which is marked by elevated serum levels of pro-inflammatory cytokines/chemokines such as tumor necrosis factor alpha (TNF-a), IL-6, IL-8 and monocyte chemoattractant protein-1, enhances disease progression owing to the recruitment of neutrophils, monocytes and macrophages. [10][11][12][13] Although a role for Kupffer cells and neutrophils in the progression of ALD is acknowledged, 10,11,13 there is much to be understood regarding how various immune cells interact and contribute to alcohol-induced liver injury.…”