No abstract

Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.

No abstract

The antioxidant effect of caffeine, associated with its ability to upregulate the nuclear factor-E2-related factor-2 (Nrf2)-signaling pathway, was explored as a possible mechanism for the attenuation of liver damage. Nonalcoholic steatohepatitis (NASH) was induced in rats by the administration of a high-fat, high-sucrose, high-cholesterol diet (HFSCD) for 15 weeks. Liver damage was induced in rats by intraperitoneal administration of thioacetamide (TAA) for six weeks. Caffeine was administered orally at a daily dose of 50 mg/kg body weight during the period of NASH induction to evaluate its ability to prevent disease development. Meanwhile, rats received TAA for three weeks, after which 50 mg/kg caffeine was administered daily for three weeks with TAA to evaluate its capacity to interfere with the progression of hepatic injury. HFSCD administration induced hepatic steatosis, decreased Nrf2 levels, increased oxidative stress, induced the activation of nuclear factor-κB (NF-κB), and elevated proinflammatory cytokine levels, leading to hepatic damage. TAA administration produced similar effects, excluding steatosis. Caffeine increased Nrf2 levels; attenuated oxidative stress markers, including malondialdehyde and 4-hydroxynonenal; restored normal, reduced glutathione levels; and reduced NF-κB activation, inflammatory cytokine levels, and damage. Our findings suggest that caffeine may be useful in the treatment of human liver diseases.

While non-alcoholic fatty liver disease (NAFLD) without inflammation or fibrosis is considered a relatively ‘benign’ disease, non-alcoholic steatohepatitis (NASH), by contrast, is characterized by marked inflammation in addition to lipid accumulation, and may include fibrosis, progression to cirrhosis and hepatocellular carcinoma. Obesity and type II diabetes are frequently associated with NAFLD/NASH; however, a significant number of lean individuals may develop these diseases. Little attention has been paid to the causes and mechanisms contributing to NAFLD development in normal-weight individuals. One of the main causes of NAFLD in normal-weight individuals is the accumulation of visceral and muscular fat and its interaction with the liver. Myosteatosis (triglyceride accumulation in the muscle) induces a loss of muscle by reducing blood flow and insulin diffusion, contributing to NAFLD. Normal-weight patients with NAFLD exhibit higher serum markers of liver damage and C-reactive protein levels, as well as more pronounced insulin resistance, compared to healthy controls. Notably, increased levels of C-reactive protein and insulin resistance are strongly correlated with the risk of developing NAFLD/NASH. Gut dysbiosis has also been associated with NAFLD/NASH progression in normal-weight individuals. More investigation is required to elucidate the mechanisms leading to NAFLD in normal-weight individuals.