Developmental Programming of Nonalcoholic Fatty Liver Disease

Developmental programming describes the process by which exposures during critical windows of early life—for example, maternal nutrition, in utero stressors or paternal factors—induce lasting changes in gene expression, metabolism, immune function and microbiome composition. In the context of nonalcoholic fatty liver disease (NAFLD), these early‐life cues alter hepatic lipid handling, inflammatory responses and fibrotic pathways, thereby setting a trajectory towards steatosis and liver injury in later life. Epigenetic modifications, shifts in microbial colonisation and dysregulated signalling through key metabolic sensors collectively underpin this predisposition. Understanding how perinatal interventions—ranging from dietary optimisation to maternal exercise—can mitigate these programmed risks offers a promising avenue to curb the global rise in NAFLD and its complications.

Research from Nature Portfolio

Recent studies have demonstrated that maternal obesity–associated dysbiosis in the neonatal gut directly contributes to hepatic inflammation and accelerates steatosis in offspring. In germ‐free models colonised with microbiota from infants of obese mothers, there is an upregulation of endoplasmic reticulum stress and innate immune genes in the liver, increased intestinal permeability and impaired macrophage function; exposure to a Western‐style diet further accelerates NAFLD development. In parallel, investigations into maternal exercise during pregnancy reveal that offspring of physically active dams show early activation of AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha and PPARγ coactivator-1α in the liver. This reprogramming reduces lipogenesis and enhances β-oxidation at a critical postnatal stage, reshaping the hepatic proteome—most notably via increased cholesterol 7α-hydroxylase expression—and conferring protection against high-fat-diet–induced steatosis in adulthood.

Developmental Programming of Nonalcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in developmental programming of nonalcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Developmental programming: The process by which environmental influences during prenatal and early postnatal life induce permanent changes in physiology and disease susceptibility.

Nonalcoholic fatty liver disease (NAFLD): A spectrum of liver conditions characterised by excess fat accumulation in hepatocytes in the absence of significant alcohol intake, ranging from simple steatosis to nonalcoholic steatohepatitis and fibrosis.

Epigenetic modification: A biochemical change to DNA or associated proteins that alters gene expression without changing the underlying DNA sequence, often in response to environmental cues.

Gut microbiome dysbiosis: An imbalance in the composition or function of intestinal microbial communities, which can influence host metabolism and immune responses.

AMP-activated protein kinase (AMPK): A cellular energy sensor that, when activated, promotes catabolic pathways such as fatty acid oxidation and inhibits anabolic processes like lipogenesis.

Peroxisome proliferator-activated receptor alpha (PPARα): A nuclear receptor that regulates genes involved in fatty acid transport, β-oxidation and lipid metabolism.

References

1. Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice. Food Frontiers (2024).
2. The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nature Communications (2018).
3. Developmental Programming of Nonalcoholic Fatty Liver Disease: The Effect of Early Life Nutrition on Susceptibility and Disease Severity in Later Life. BioMed Research International (2015).
4. Maternal obesity increases the risk and severity of NAFLD in offspring. Journal of Hepatology (2021).
5. Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming. Scientific Reports (2020).