Fig. 1
Adapted from Godoy-Matos et al.
Pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). Environmental factors affect the expression of genes, inducing weight gain. When the capacity to expand subcutaneous adipose tissue (AT) is reached, increased free fatty acid (FFA) deposition occurs in visceral and ectopic sites. One ectopic site is the muscle, where increased FFA deposition promotes insulin resistance (IR), inhibiting insulin-mediated glucose uptake. On the other hand, AT insulin resistance facilitates lipolysis and increases the flux of FFAs to the liver, inducing hepatic IR and enhancing glucose production, de novo hepatic lipogenesis, VLDL release and atherogenic dyslipidemia. FFAs spill over into the pancreas, facilitating β-cell dysfunction through lipotoxicity, hyperglycemia and diabetes (the twin cycle hypothesis). Increased liver fat also promotes hepatic glucagon resistance (GR) through amino acid (AA) metabolism, reducing ureagenesis and resulting in hyperaminoacidemia. Increased AAs stimulate glucagon production to compensate for hepatic GR, and a vicious cycle occurs (the liver-pancreas axis). This hyperglucagonemia also leads to increased hepatic glucose release. A global IR state results in hyperinsulinemia, which may enhance sodium reabsorption and increase sympathetic nervous system activity, contributing to hypertension. Inflamed dysfunctional AT leads to increased insulin resistance, the release of proinflammatory adipokines, and decreased levels of the anti-inflammatory agent adiponectin. In the liver, triglycerides and toxic metabolites induce lipotoxicity, mitochondrial dysfunction and endoplasmic reticulum stress, leading to hepatocyte damage, apoptosis, and fibrosis. These dysfunctional hepatocytes synthesize and secrete dipeptidyl peptidase 4 (DPP4), which promotes inflammation in AT macrophages and increased IR. AA amino acids, AT adipose tissue, DPP4 dipeptidyl peptidase 4, FFA free fatty acid, GR glucagon resistance, HDL high-density lipoprotein, IR insulin resistance, LDL low-density lipoprotein, MASLD metabolic dysfunction-associated steatotic liver disease, SAT subcutaneous adipose tissue, SNS sympathetic nervous system, VAT visceral adipose tissue, VLDL very low-density lipoprotein. Pointed arrows indicate stimulation or enhancement, while blunt ends indicate inhibition or repression. Dashed arrows indicate progressive reductions in a pathway. [2]