Canonical and Non-Canonical Regulators of Lipid Metabolism in the Liver and the “Liver–Other Organs” Axes

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease and is closely associated with obesity, insulin resistance, and the recently conceptualized cardiovascular–kidney–metabolic syndrome. For decades, the pathogenesis of steatosis has been viewed primarily through the lens of insulin and the canonical transcriptional programs it regulates—sterol regulatory element-binding protein 1c, carbohydrate response element-binding protein, peroxisome proliferator-activated receptors, and AMP-activated protein kinase. At the same time, recent data point to the existence of a complex network of non-canonical regulators that, independently of insulin, significantly modulate hepatic lipid metabolism. This review systematizes information on the fibroblast growth factors FGF21 and FGF19, adipokines (adiponectin, leptin), apolipoprotein C-III, as well as the monoamine neurotransmitters serotonin and dopamine. These molecules act within the interorgan axes “liver–adipose tissue,” “gut–liver,” “brain–liver,” and “liver–spleen,” coordinating lipolysis, gluconeogenesis, very-low-density lipoprotein secretion, inflammation, and fibrogenesis. Disruption of the dynamic balance between canonical and non-canonical regulators is central to the progression from simple steatosis to steatohepatitis and fibrosis. The clinical translation of this concept has already begun: the thyroid hormone receptor β agonist resmetirom and the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide have received regulatory approval for specific categories of patients with noncirrhotic metabolic dysfunction-associated steatohepatitis and fibrosis, while FGF21 and FGF19 analogs, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonist tirzepatide, and agents targeting apolipoprotein C-III are at various stages of clinical development or are being used for related metabolic indications. Expanding the insulin-centric paradigm to include non-canonical axes opens up new diagnostic and therapeutic possibilities for MASLD.