Pathophysiology and Management of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions characterised by excessive lipid accumulation in hepatocytes in the absence of excessive alcohol intake. The initial phase, steatosis, reflects simple fat deposition, which may progress to non-alcoholic steatohepatitis (NASH) when accompanied by inflammation, hepatocyte injury and early fibrosis. Central to this progression are insulin resistance, dysregulation of lipid metabolism and oxidative stress, which collectively promote fibrogenesis and, in advanced cases, cirrhosis and hepatocellular carcinoma. Pathogenic mechanisms include enhanced de novo lipogenesis, mitochondrial dysfunction with excess reactive oxygen species, endoplasmic reticulum stress and proinflammatory signalling within the hepatic microenvironment. Management currently relies on weight reduction through lifestyle modification, optimisation of metabolic risk factors such as glycaemic control and lipid profiles, and surveillance for progressive fibrosis using noninvasive tools. Emerging strategies target specific molecular pathways—such as inhibitors of de novo lipogenesis, agents modulating immune cell function and interventions directed at the gut–liver axis—while precision medicine approaches harness genetic and organoid models to identify novel therapeutic candidates.

Research from Nature Portfolio

Recent studies have leveraged human hepatocyte organoids to model early steatosis and enable high-throughput screening of candidate compounds. Using a bespoke CRISPR-based platform, researchers induced steatosis through free fatty acid loading, genetic variants of PNPLA3 and monogenic lipid disorder mutations. Screening of lipid modulatory genes identified fatty acid desaturase 2 (FADS2) as a key regulator whose upregulation increases polyunsaturated fatty acid levels and suppresses de novo lipogenesis. This organoid system offers a powerful tool for mechanistic interrogation of steatosis and for prioritising drug targets in a human-relevant context.

Pathophysiology and Management of Non-Alcoholic Fatty Liver Disease publication trend

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

Technical terms

Steatosis: Excessive accumulation of triglycerides within hepatocytes, the initial stage of disease.

Non-alcoholic steatohepatitis (NASH): Inflammatory progression of steatosis characterised by hepatocyte injury and varying degrees of fibrosis.

Fibrosis: Pathological deposition of extracellular matrix components in the liver, leading to tissue stiffness and impaired function.

De novo lipogenesis: Hepatic synthesis of fatty acids from non-lipid precursors, contributing to intracellular lipid surplus.

Organoid: Three-dimensional in vitro culture model that recapitulates key structural and functional features of liver tissue.

References

1. Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis. The Lancet Gastroenterology & Hepatology (2023).
2. Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis. Nature Biotechnology (2023).
3. Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells. Molecular Cancer (2024).
4. Changing epidemiology, global trends and implications for outcomes of NAFLD. Journal of Hepatology (2023).