Metabolic Modulation in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis, driven by excess lipid accumulation, insulin resistance and chronic inflammation. Central to its pathogenesis is an imbalance between lipid uptake, de novo lipogenesis and fatty acid oxidation, compounded by mitochondrial dysfunction and endoplasmic reticulum stress. Crosstalk between hepatocytes, immune cells and hepatic stellate cells orchestrates progression towards fibrotic remodelling. Therapeutic strategies have therefore focused on metabolic modulation: activating nuclear receptors such as peroxisome proliferator-activated receptor alpha (PPARα) to enhance β-oxidation, promoting autophagy to clear lipid droplets, and attenuating pro-inflammatory signalling. Recent advances also highlight the role of gut-liver communication, with intestinal factors shaping hepatic lipid handling and inflammation. With NAFLD prevalence rising globally, interventions that safely recalibrate metabolic pathways hold promise for both prevention and treatment.

Research from Nature Portfolio

Recent studies using a novel serial section-3D (SS3D) imaging approach have enabled unprecedented three-dimensional visualisation of fibrotic regions in a mouse model of NASH. By combining high-resolution imaging with quantitative reconstruction software, investigators demonstrated that a high-fat diet followed by lipopolysaccharide administration doubles the volume of fibrotic tissue compared with controls. Mechanistic experiments revealed that latent transforming growth factor-β1 produced in fatty liver is activated by macrophage-derived inflammatory cytokines (TNFα and IL-1β), leading to hepatic stellate cell activation and elevated collagen I production. This work not only elucidates a key inflammatory axis in fibrosis progression but also establishes a versatile SS3D platform for studying tissue remodelling in metabolic liver disease.

Metabolic Modulation in Non-Alcoholic Fatty Liver Disease publication trend

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

Technical terms

Steatosis: accumulation of lipid droplets within hepatocytes.
Fibrosis: excessive deposition of extracellular matrix proteins in the liver.
Autophagy: intracellular process for degradation of cellular components to maintain homeostasis.
Hepatic stellate cells: liver cells that, when activated, produce collagen leading to fibrosis.
Lipotoxicity: cellular dysfunction and death caused by accumulation of toxic lipid species.
Transcriptomics: study of the complete set of RNA transcripts produced by the genome.
Metabolomics: analysis of the full complement of small-molecule metabolites within a biological sample.

References

1. Assessing the combined impact of fatty liver-induced TGF-β1 and LPS-activated macrophages in fibrosis through a novel 3D serial section methodology. Scientific Reports (2024).
2. Ferulic Acid Prevents Nonalcoholic Fatty Liver Disease by Promoting Fatty Acid Oxidation and Energy Expenditure in C57BL/6 Mice Fed a High-Fat Diet. Nutrients (2022).
3. Red Rice Bran Extract Alleviates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease and Dyslipidemia in Mice. Nutrients (2023).
4. New insights into the hepato-protective effects of ferulic acid based on transcriptomic and metabolomic profiling. Journal of Functional Foods (2024).