Metabolic-Associated Fatty Liver Disease and Insulin Resistance: A Review of Complex Interlinks

Abstract

Metabolic-associated fatty liver disease (MAFLD) has now surpassed alcohol excess as the most common cause of chronic liver disease globally, affecting one in four people. Given its prevalence, MAFLD is an important cause of cirrhosis, even though only a small proportion of patients with MAFLD ultimately progress to cirrhosis. MAFLD suffers as a clinical entity due to its insidious and often asymptomatic onset, lack of an accurate and reliable non-invasive diagnostic test, and lack of a bespoke therapy that has been designed and approved for use specifically in MAFLD. MAFLD sits at a crossroads between the gut and the periphery. The development of MAFLD (including activation of the inflammatory cascade) is influenced by gut-related factors that include the gut microbiota and intactness of the gut mucosal wall. The gut microbiota may interact directly with the liver parenchyma (through translocation via the portal vein), or indirectly through the release of metabolic metabolites that include secondary bile acids, trimethylamine, and short-chain fatty acids (such as propionate and acetate). In turn, the liver mediates the metabolic status of peripheral tissues (including insulin sensitivity) through a complex interplay of hepatokines, liver-secreted metabolites, and liver-derived micro RNAs. As such, the liver plays a key central role in influencing overall metabolic status. In this concise review, we provide an overview of the complex mechanisms whereby MAFLD influences the development of insulin resistance within the periphery, and gut-related factors impact on the development of MAFLD. We also discuss lifestyle strategies for optimising metabolic liver health.

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Due to this, SHBG is present at reduced rates in individuals with hepatic steatosis. This occurs since lipogenesis, the main pathway that results in the accumulation of ILH (intrahepatic lipids), reduces the expression of hepatocyte nuclear factor 4α-responsible for SHBG transcription-resulting in a reduction in its expression [170,171]. Concerning lipid metabolism, the overexpression of SHBG protects against the development of MAFLD, inhibiting hepatic lipogenesis by controlling the main lipogenic enzymes.…”

“…171,178] ANGPTL-4: Angiopoietin-Like 4; BMP: Bone Morphogenetic Protein; IL: Interleukin; MAFLD: metabolicassociated fatty liver disease; LECT 2: Leukocyte Cell-Derived Chemotaxin; NF-κβ: Nuclear Factor κβ; SHBG: Sexual Hormone-Binding Globulin; TNF-α: Tumor Necrosis Factor-α; VCAM: Vascular cell adhesion protein 1.…”

New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut–Liver–Heart Crosstalk

“…MAFLD poses a substantial economic burden, as well as implications for clinical diagnosis, management, and the molecular mechanisms that link it to end-stage liver disease or cancer [ 3 , 4 ]. Its pathogenesis is complex and involves various factors, such as hepatic immune cells, insulin resistance, gut-related factors, and lifestyle choices [ 5 ]. Further research is needed to gain a deeper insight into the pathogenesis, prognosis, and therapeutic options for MAFLD.…”