Canonical and Non-Canonical Regulators of Lipid Metabolism in the Liver and the "Liver-Other Organs" Axes.
4 affiliations
- 1Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia.
- 2Department of Pharmaceutical Technology and Pharmacy Practice Administration, Ryazan State Medical University, 390026 Ryazan, Russia.
- 3Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.
- 4Regenera R&D International for Aging Intervention, 20154 Milano, Italy.
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.
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BibTeX
@article{kotlyarov2026canonical,
title = {{Canonical and Non-Canonical Regulators of Lipid Metabolism in the Liver and the "Liver-Other Organs" Axes.}},
author = {Stanislav Kotlyarov and Anna Kotlyarova and Roberto Catanzaro and Francesco Marotta},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198614},
url = {https://europepmc.org/article/MED/42883860},
note = {CC BY},
}
RIS
TY - JOUR
TI - Canonical and Non-Canonical Regulators of Lipid Metabolism in the Liver and the "Liver-Other Organs" Axes.
AU - Stanislav Kotlyarov
AU - Anna Kotlyarova
AU - Roberto Catanzaro
AU - Francesco Marotta
PY - 2026
DA - 2026/09/26
JO - International journal of molecular sciences
DO - 10.3390/ijms27198614
UR - https://europepmc.org/article/MED/42883860
AB - 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.
SN - 1422-0067
ER -