Metabolic Regulation in Liver Diseases

Metabolic regulation in liver diseases encompasses the intricate control of glucose, lipid and energy homeostasis within hepatocytes and non-parenchymal cells. Central enzymes and sensors such as AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptors (PPARs) integrate hormonal and nutrient signals to balance gluconeogenesis, lipogenesis and fatty acid oxidation. Disruption of this balance by overnutrition, insulin resistance, chronic inflammation or oxidative stress drives the spectrum of non-alcoholic fatty liver disease (NAFLD), progression to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Emerging studies have illuminated roles for nucleotide release channels, kinase–phosphatase modules and transcriptional networks in modulating hepatocyte survival, inflammation and extracellular matrix deposition. With NAFLD now affecting nearly a quarter of the global population and no licensed drug for NASH, elucidation of metabolic nodes has become imperative. Therapeutic strategies aim to restore energy sensing and substrate flux, combining lifestyle interventions with agents targeting AMPK activation, nuclear receptor modulation and gut–liver signalling. Advances in multi-omic profiling and refined preclinical models promise precision approaches for diagnosis, monitoring and personalised treatment of liver disorders through restoration of metabolic equilibrium.

Research from Nature Portfolio

Recent studies have identified a nuclear-localised mitogen-activated protein kinase phosphatase that suppresses AMPKα activity by retaining liver kinase B1 (LKB1) within the nucleus under steatohepatitis conditions. This retention inhibits cytoplasmic AMPK activation, promoting hepatocyte death, inflammation and fibrotic remodelling characteristic of NASH. Hepatic deletion of the phosphatase restores LKB1-mediated AMPKα activation, reduces cell death and attenuates fibrosis in dietary models. This signalling axis offers a novel target to reinstate energy sensing, protect hepatocytes and prevent progression from sterile inflammation to fibrogenesis in chronic liver disease.

Metabolic Regulation in Liver Diseases publication trend

The graph below shows the total number of articles in metabolic regulation in liver diseases across all publications each year (not limited to Nature Index journals).

Technical terms

AMP-activated protein kinase (AMPK): A cellular energy sensor that maintains energy homeostasis by switching off anabolic pathways and activating catabolic processes.

Gluconeogenesis: The metabolic pathway by which glucose is synthesised de novo from non-carbohydrate precursors in the liver.

Lipogenesis: The biochemical process of fatty acid and triglyceride synthesis within hepatocytes.

Non-alcoholic steatohepatitis (NASH): An advanced form of NAFLD characterised by hepatocyte injury, inflammation and varying degrees of fibrosis.

Hepatic stellate cells: Liver-resident cells that, upon activation by injury or inflammation, secrete extracellular matrix proteins leading to fibrosis.

Pannexin 1 (PANX1) channels: Membrane proteins that mediate release of ATP into the extracellular space, facilitating purinergic signalling.

Fibrosis: The pathological accumulation of extracellular matrix components in the liver, resulting in tissue scarring and impaired function.

References

1. PANX1-mediated ATP release confers FAM3A’s suppression effects on hepatic gluconeogenesis and lipogenesis. Military Medical Research (2024).
2. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nature Communications (2023).
3. Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options. Cardiovascular Research (2023).
4. The AMPK pathway in fatty liver disease. Frontiers in Physiology (2022).