Associations of altered hepatic gene expression in American lifestyle-induced obesity syndrome diet-fed mice with metabolic changes during NAFLD development and progression.

Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains poorly understood due to the complex metabolic and inflammatory changes in the liver. This study aimed to elucidate hepatic events related to inflammation and lipid metabolism and their linkage with metabolic alterations during NAFLD in American lifestyle-induced obesity syndrome (ALIOS) diet-fed mice. Forty-eight C57BL/6J male mice were fed with ALIOS diet (n=24) or control chow diet (n=24) for 8, 12, and 16 weeks. At the end of each timepoint, eight mice were sacrificed where plasma and liver were collected. Hepatic fat accumulation was followed using magnetic resonance imaging and confirmed with histology. Further, targeted gene expression and non-targeted metabolomics analysis were conducted. Our results showed higher hepatic steatosis, body weight, energy consumption, and liver mass in ALIOS diet-fed mice compared to control mice. ALIOS diet altered expression of genes related to inflammation (Tnfa and IL-6) and lipid metabolism (Cd36, Fasn, Scd1, Cpt1a, and Ppara). Metabolomics analysis indicated decrease of lipids containing polyunsaturated fatty acids such as LPE(20:5) and LPC(20:5) with increase of other lipid species such as LPI(16:0) and LPC(16:2) and peptides such as alanyl-phenylalanine and glutamyl-arginine. We further observed novel correlations between different metabolites including sphingolipid, lysophospholipids, peptides, and bile acid with inflammation, lipid uptake and synthesis. Together with the reduction of antioxidant metabolites and gut microbiota-derived metabolites contribute to NAFLD development and progression. The combination of non-targeted metabolomics with gene expression in future studies can further identify key metabolic routes during NAFLD which could be the targets of potential novel therapeutics.

The Lasting Effects of COVID-19 on the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

It is estimated that around 30% of the population living in Western countries has metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of pathology (not attributed to alcohol/substance intake) initiated by steatosis and progression toward inflammation and irreversible fibrosis metabolic dysfunction-associated steatohepatitis (MASH). With inflammation being a key component of the transition to MASH, it raises the question of whether the ongoing COVID-19 pandemic, which has notoriously induced hyperinflammatory states, may influence the progression of MASLD. Specifically, it remains unclear if the potential chronic sequelae of COVID-19 in patients who recovered from it may increase the predisposition for MASH. Since MASH maintains a high risk for hepatocellular carcinoma, liver failure, and the need for a liver transplant, the potential additive effects of COVID-19 could prove critical to study. Thus, the objective of this study was to conduct a literature review to examine if COVID-19 could have chronic sequelae that affect the progression of MASLD pathogenesis. It was hypothesized that severe cases of COVID-19 could induce systemic inflammation, metabolic changes, and lasting gut microbiome alterations that lead to inflammatory and fibrotic changes in the liver, similar to those seen in MASH. A scoping review of the literature was conducted utilizing the PubMed database. Studies that examined hepatobiliary pathology, gut microbiome, systemic inflammation, metabolic changes, drug-induced liver injury (DILI), and hypoxia seen in COVID-19 were included. Human studies of adult cohorts, animal models, and in vitro experiments were included. Genetic components of MASLD were not examined. Exclusion criteria also encompassed any studies not referencing the hepatobiliary, gastrointestinal tract, portal system, or systemic circulation. Findings indicated a frequent trend of elevated liver enzymes, mild steatosis, Kupffer cell hyperplasia, and hepatobiliary congestion. It was found that direct cytopathic effects on hepatocytes were unlikely, but the direct viral insult of cholangiocytes was a potential complication. High serum levels of IL-1, TNF-a, and MCP-1, in COVID-19 were found as potential risk factors for MASH development. Hypoxia, altered lipid metabolism, and iatrogenic DILI were also proposed as potential precipitators of MASH development. Notably, lasting changes in gut microbiome were also frequently observed and correlated closely with those seen in MASH.

Role of Nutrition in the Pathogenesis and Prevention of Non-alcoholic Fatty Liver Disease: Recent Updates.

Non-alcoholic fatty liver disease (NAFLD) is an acquired metabolic disease characterized by triglycerides (TGs) deposition in liver induced by other factors rather than alcohol consumption. NAFLD significantly contributes to liver diseases in children and adults. NAFLD pathogenesis is associated with age, gender, race and ethnicity. Insulin resistance, hyperinsulinemia, elevated plasma free fatty acids (FFAs), fatty liver, hepatocyte injury, liver inflammation, oxidative stress, mitochondrial dysfunction, imbalanced pro-inflammatory cytokines, and fibrosis are the characteristics of NAFLD. Factors including genetic and epigenetic pathways, sedentary lifestyle, sleep, and diet composition affect NAFLD pathogenesis. In this review, we discuss the aetiology, risk factors and pathogenesis of NAFLD. Special focus is given to macro and micro nutrition as causing factors and their role in the prevention of NAFLD pathogenesis.