Metabolic Mechanisms in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic disorders characterised by the accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption. Central to its pathogenesis is an imbalance between lipid acquisition—driven by increased uptake of non-esterified fatty acids from adipose tissue and elevated de novo lipogenesis—and lipid disposal, comprising mitochondrial β-oxidation and very-low-density lipoprotein secretion. Insulin resistance amplifies hepatic lipid synthesis through hyperinsulinaemia-mediated activation of sterol regulatory element-binding protein-1c and carbohydrate-responsive element-binding protein, while failing to suppress adipose lipolysis. The ensuing lipotoxicity triggers endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress, which in turn initiate inflammatory cascades and fibrogenesis. Perturbations in iron metabolism and gut-liver axis mediators further modulate disease progression. As steatosis advances to non-alcoholic steatohepatitis, chronic injury and repair mechanisms drive extracellular matrix deposition, predisposing to cirrhosis and hepatocellular carcinoma. A comprehensive understanding of these interlinked metabolic pathways is vital for the development of targeted interventions to halt or reverse disease progression.

Research from Nature Portfolio

Recent studies have examined the relationship between gut-derived metabolites and hepatic lipid homeostasis, revealing that elevated circulating levels of trimethylamine-N-oxide correlate with both the presence and severity of hepatic steatosis. In parallel, alterations in the balance of betaine and choline have been shown to influence liver fat accumulation, suggesting that modulation of microbiota-dependent methylamine metabolism may represent a novel approach to attenuating lipid overload in hepatocytes.

Metabolic Mechanisms in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in metabolic mechanisms in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

De novo lipogenesis: The metabolic pathway by which hepatocytes synthesise fatty acids from acetyl-CoA precursors, primarily derived from carbohydrate catabolism.

Insulin resistance: A physiological state in which target tissues become less responsive to insulin, leading to impaired glucose disposal and dysregulated lipid metabolism.

Hepatic steatosis: The accumulation of lipid droplets, predominantly triglycerides, within hepatocytes, marking the earliest stage of NAFLD.

Oxidative stress: An imbalance between reactive oxygen species production and antioxidant defences, resulting in cellular damage and activation of inflammatory pathways.

Lipotoxicity: Cellular injury induced by the accumulation of toxic lipid species, such as free fatty acids and ceramides, which disrupt organelle function and promote apoptosis.

References

1. Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH). International Journal of Molecular Sciences (2013).
2. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Scientific Reports (2016).
3. Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease. Signal Transduction and Targeted Therapy (2024).
4. Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease. Military Medical Research (2023).
5. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. Journal of Gastroenterology (2013).