The physiology of MASLD: molecular pathways between liver and adipose tissues

The global prevalence of obesity has exerted a profound influence on human health. It has contributed to numerous obesity-related comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and insulin-resistant diabetes. MASLD is diagnosed when there is substantial fat accumulation concomitant with five additional diagnostic criteria. If untreated, MASLD may progress to liver fibrosis and cirrhosis, conditions that can be life-threatening in the final stages. Nonetheless, the development and progression of MASLD are complex, and its underlying mechanisms remain incompletely elucidated. Typically, during fasting, adipose tissue releases fatty acids, which the liver subsequently uptakes for gluconeogenesis. However, this process, along with many others, is impaired in the liver and adipose tissue of individuals with MASLD. This review provides comprehensive details on the mechanisms underlying adiposity and insulin resistance associated with MASLD. We discuss the canonical pathways that promote lipogenesis and insulin sensitivity in the liver and adipose tissues, including bile acids, bilirubin, fatty acids, inflammation, de novo lipogenesis, oxidative stress, peroxisome proliferator-activated receptors (PPARs), fibroblast growth factor 21 (FGF21), glucagon-like peptide 1 (GLP1), and metabolism of fructose. The scope of the review is expanded to encompass biological responses to fasting and feeding, as well as their effects on fat accumulation and insulin sensitivity in these tissues. Additionally, the review elaborates on critical molecular mechanisms regulating MASLD progression, including hepatic insulin clearance, insulin degradation, bilirubin metabolism, nerve innervation, and the roles of cytokines and adipokines. Overall, this review examines the mechanisms driving MASLD and explores potential novel therapeutic strategies for its management.