Work

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

Year: 2026

Type: review

Abstract: 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.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27198614

Authors: Stanislav Kotlyarov, Anna Kotlyarova, Roberto Catanzaro, Francesco Marotta

Institutions: Ryazan State Medical University named after Academician I.P. Pavlov, University of Catania

Language: English

Topic: Liver Disease Diagnosis and Treatment

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499