Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease

Abstract

Background & Aims Alcohol‐related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl‐fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. Methods Dimethyl‐fumarate or vehicle was orally administered to wild‐type mice receiving a Lieber‐DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical‐ and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol‐induced intestinal barrier disruption. Results Dimethyl‐fumarate protected against ethanol‐induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines ( Tnf‐α, Il‐1β, Cxcl1 ) and reduced abundance of neutrophils and macrophages in ethanol‐fed and DMF‐treated mice when compared to vehicle. DMF protected against ethanol‐induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS‐induced cytokine responses of KCs. Conclusions Dimethyl‐fumarate counteracts ethanol‐induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.

DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD

“…Actually, we and other groups revealed that mild hepatic steatosis, inflammation, and injury could be observed for a few days after the construction of an ALD mouse model. 32,33 We found that the level of DRAM1 in liver tissues of mice fed with an ethanol diet was significantly increased at 3 days and was relatively high, though not significantly, at 1 week. These data suggested that the level of DRAM1 was evaluated at the early stage during ethanol-induced hepatic steatosis, injury, and inflammation.…”

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

“…The alterations of intestinal microbiota have been described as the driving force of ALD development, 13 , 31 , 32 and in some experimental models, oral supplementation with probiotics, bacteria, and some immunomodulatory molecules attenuated liver alcohol-related liver 16 , 33 , 34 injury. Ethanol ingestion provokes leaky gut and bacterial overgrowth through disruption of mucus layer and tight junction, and downregulation of antimicrobial peptides, such as Reg3b and Reg3g lectins.…”

A Novel Nutraceuticals Mixture Improves Liver Steatosis by Preventing Oxidative Stress and Mitochondrial Dysfunction in a NAFLD Model

“…Hepatic triglyceride content was analyzed as previously described [ 15 ]. Briefly, frozen liver tissue was homogenized in PBS, adjusting the volume to the weight, and incubated for 30 min at 95 °C.…”