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Developmental origins of nonalcoholic fatty liver disease
David E Brumbaugh1, Jacob E Friedman2
1Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
Insights
Maternal obesity can lead to generational nonalcoholic fatty liver disease (NAFLD) in offspring. This occurs through metabolic programming and epigenetic changes, increasing NAFLD risk across generations.
Area of Science:
- Reproductive biology
- Metabolic disorders
- Hepatology
Background:
- Maternal obesity poses risks for offspring metabolic health.
- Early childhood obesity is a predictor for nonalcoholic fatty liver disease (NAFLD).
- Fetal vulnerability to steatosis is heightened by immature adipose depots in maternal obesity.
Purpose of the Study:
- To investigate the intergenerational transmission of metabolic phenotypes from obese mothers to offspring.
- To explore the mechanisms by which maternal obesity primes offspring liver for NAFLD development.
- To examine the role of in utero exposure and epigenetic factors in NAFLD predisposition.
Main Methods:
- Review of animal models demonstrating effects of in utero high-fat diet exposure on offspring liver.
- Analysis of human studies correlating maternal BMI with infant intrahepatocellular lipid storage.
- Exploration of potential epigenetic and microbiota-mediated transmission pathways.
Main Results:
- In utero high-fat diet exposure in animal models increases offspring liver triglycerides, oxidative stress, and apoptosis.
- Postweaning offspring livers exhibit NAFLD-like features, including altered lipogenesis and fatty acid oxidation.
- Human studies confirm maternal BMI predicts infant liver lipid accumulation.
Conclusions:
- Maternal obesity can program offspring for NAFLD through metabolic and epigenetic changes.
- The generational transfer of NAFLD risk is influenced by in utero environment and potentially microbiota.
- Early life interventions may be crucial to mitigate intergenerational NAFLD transmission.
Abstract:
Obese pregnant women may transmit their metabolic phenotype to offspring, leading to a cycle of obesity and diabetes over generations. Early childhood obesity predicts nonalcoholic fatty liver disease (NAFLD), the most common chronic human liver disease. The fetus may be vulnerable to steatosis because immature fetal adipose depots are not available to buffer the excess transplacental lipid delivery in maternal obesity. In animal models, in utero high-fat diet exposure results in an increase in the accumulation of liver triglycerides in offspring and increased hepatic oxidative stress and apoptosis, perhaps priming the liver for later development of NAFLD. Innate immune dysfunction and necroinflammatory changes have been observed in postnatal offspring liver of animals born to high-fat-fed dams. Postweaning, livers of offspring exposed to maternal high-fat feeding in utero share pathophysiologic features with human NAFLD, including increased de novo lipogenesis and decreased free fatty acid oxidation. Human studies using magnetic resonance imaging have shown that maternal BMI predicts infant intrahepatocellular lipid storage, as seen in animal models. The generational transfer of NAFLD may occur via epigenetic changes in offspring liver. Transmission of microbiota from mother to infant may impact energy retention and immune function that contribute to a predisposition to NAFLD.
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