Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications

Table 1 Core metabolic differences between obesity-related and lean metabolic dysfunction-associated steatotic liver disease

Characteristic	Obesity-related MASLD	Lean MASLD
Primary initiating factors	Systemic IR, overnutrition	Genetic variants, dysfunctional visceral adipose tissue, and gut-liver axis dysregulation
FFA source	Peripheral lipolysis	Visceral adipose tissue, gut microbiota-derived metabolites
DNL	Enhanced	Enhanced
Fatty acid oxidation	Impaired	May be markedly reduced
VLDL	Early compensatory increase (relative insufficiency), later absolute insufficiency	Genetic secretion defects (e.g., TM6SF2 variants) or normal
Inflammatory triggers	Early adipose tissue macrophage activation, later accompanied by hepatic innate immune activation	Gut-derived LPS translocation, hepatic innate immune activation
Genetic predisposition	Polygenic susceptibility with cumulative minor effects	Monogenic strong effects (e.g., PNPLA3)
Prognosis	Higher incidence of cardiovascular complications	Higher incidence of liver disease and all-cause mortality
Clinical management focus	Weight reduction, improving IR, managing metabolic syndrome	Fructose restriction, correcting malnutrition, targeted genetic interventions

MASLD: Metabolic dysfunction-associated steatotic liver disease; IR: Insulin resistance; FFA: Free fatty acid; DNL: De novo lipogenesis; VLDL: Very low-density lipoprotein; TM6SF2: Transmembrane 6 superfamily member 2; LPS: Lipopolysaccharide; PNPLA3: Patatin-like phospholipase domain-containing protein 3.