Metabolic Dysfunction in Hepatic Disease

Metabolic dysfunction in hepatic disease encompasses a spectrum of disturbances in lipid, carbohydrate and energy metabolism that underlie conditions from simple steatosis to cirrhosis and hepatocellular carcinoma. Central to this dysfunction is an imbalance between fatty acid uptake, de novo lipogenesis and β-oxidation, leading to intrahepatic triglyceride accumulation. Insulin resistance exacerbates hepatic lipid deposition by impairing suppression of gluconeogenesis and enhancing lipolysis in adipose depots. Mitochondrial adaptations—such as altered tricarboxylic acid cycle flux, impaired ketogenesis and reactive oxygen species overproduction—further drive oxidative stress, inflammation and fibrogenesis. These processes interact in a vicious cycle: excess liver fat impairs insulin signalling, which in turn worsens lipid and glucose handling across the whole body. Globally, non-alcoholic fatty liver disease affects an estimated quarter of the adult population and contributes significantly to diabetes, cardiovascular disease and liver-related mortality. Advances in metabolic phenotyping and molecular modelling are illuminating new nodes for therapeutic intervention, with the ultimate aim of restoring hepatic metabolic flexibility and preventing progression to advanced liver disease.

Research from Nature Portfolio

A genome-scale integration of transcriptomic and metabolic flux data in human liver biopsies has revealed that accumulation of fat profoundly alters adaptive responses of hepatic metabolism. Steatosis was associated with upregulation of mitochondrial pathways, increased lipolysis and glyceroneogenesis, and a shift from lactate to glycerol as a gluconeogenic substrate. Despite elevated metabolic activity, network-level analyses demonstrated reduced capacity to flexibly respond to further perturbations, suggesting that an exhausted adaptive reserve may precipitate progression to inflammation and fibrosis. This seminal work provides a systems-level framework to understand how an overloaded liver enters a maladaptive state of reduced metabolic adaptability.

Metabolic Dysfunction in Hepatic Disease publication trend

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

Technical terms

De novo lipogenesis: The synthesis of fatty acids from non-lipid precursors, mainly carbohydrates, within the liver.

Ketogenesis: The hepatic production of ketone bodies from acetyl-CoA, typically during fasting or low-carbohydrate states.

Gluconeogenesis: Generation of glucose in the liver from non-carbohydrate substrates such as glycerol and amino acids.

Tricarboxylic acid (TCA) cycle: Central mitochondrial pathway that oxidises acetyl-CoA to generate energy, reducing equivalents and intermediates for biosynthesis.

Insulin resistance: A state in which target tissues respond inadequately to normal levels of insulin, leading to impaired glucose and lipid regulation.

References

1. Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver. Journal of Clinical Investigation (2023).
2. Novel approach using [18F]FTHA-PET and de novo synthesized VLDL for assessment of FFA metabolism in a rat model of diet induced NAFLD. Clinical Nutrition (2023).
3. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease. Nature Communications (2016).
4. Metabolic Changes of Hepatocytes in NAFLD. Frontiers in Physiology (2021).