Related Experiment Video
Updated: Jan 31, 2026
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis
Luz Helena Gutierrez Sanchez1, Kyoko Tomita2, Qianqian Guo2
1Division of Pediatric Gastroenterology and Hepatology Mayo Clinic Rochester MN.
Insights
Maternal obesity-inducing diets prime offspring livers for nonalcoholic fatty liver disease (NAFLD) and fibrosis through epigenetic changes. This highlights risks for children of obese mothers.
Area of Science:
- Pediatric Gastroenterology and Hepatology
- Epigenetics and Developmental Biology
- Nutritional Science
Background:
- Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric liver disease, linked to the obesity epidemic.
- The impact of maternal obesity-inducing diets (OID) on offspring NAFLD development is not fully understood.
- Perinatal nutrition influences long-term health outcomes through epigenetic mechanisms.
Purpose of the Study:
- To investigate how perinatal exposure to an obesity-inducing diet (OID) affects the development of NAFLD in offspring.
- To explore the role of epigenetic modifications (DNA methylation) in mediating the effects of perinatal OID on liver health.
- To identify molecular pathways involved in diet-induced liver disease progression.
Main Methods:
- Breeding C57BL/6J mice were fed either a control chow or an OID rich in fat, fructose, and cholesterol (FFC) during gestation and lactation.
- Offspring were weaned to either chow or FFC diet, creating four experimental groups.
- Whole-liver transcriptome (RNA-seq) and genome-wide methylation (RRBS) were analyzed in 10-week-old mice.
Main Results:
- Perinatal OID exposure followed by an FFC diet significantly increased hepatic steatosis, injury, inflammation, and fibrosis in offspring.
- 189 differentially expressed and methylated genes were identified in offspring exposed to perinatal OID.
- Gene set enrichment analysis revealed hepatic fibrosis and stellate cell activation as key pathways, linked to DNA methylation changes.
- Mice exposed to perinatal OID but fed chow in adulthood still developed significant liver pathology when later challenged with an FFC diet.
Conclusions:
- Perinatal exposure to an OID reprograms the offspring's liver epigenome, predisposing them to an aggressive fibrosing nonalcoholic steatohepatitis (NASH) phenotype.
- These findings suggest that epigenetic modifications play a crucial role in mediating the long-term effects of maternal diet on offspring liver health.
- The study has implications for monitoring and risk-stratifying children born to obese mothers, particularly those with NAFLD.
Abstract:
With the epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The influence of a perinatal obesity-inducing diet (OID) on the development and progression of NAFLD in offspring is important but incompletely studied. Hence, we fed breeding pairs of C57BL/6J mice during gestation and lactation (perinatally) either chow or an OID rich in fat, fructose, and cholesterol (FFC). The offspring were weaned to either chow or an FFC diet, generating four groups: perinatal (p)Chow-Chow, pChow-FFC, pFFC-Chow, and pFFC-FFC. Mice were sacrificed at 10 weeks of age. We examined the whole-liver transcriptome by RNA sequencing (RNA-seq) and whole-liver genome methylation by reduced representation bisulfite sequencing (RRBS). Our results indicated that the pFFC-FFC mice had a significant increase in hepatic steatosis, injury, inflammation, and fibrosis, as assessed histologically and biochemically. We identified 189 genes that were differentially expressed and methylated in the pFFC-FFC mice versus the pChow-FFC mice. Gene set enrichment analysis identified hepatic fibrosis/hepatic stellate cell activation as the top canonical pathway, suggesting that the differential DNA methylation events in the mice exposed to the FFC diet perinatally were associated with a profibrogenic transcriptome. To verify that this finding was consistent with perinatal nutritional reprogramming of the methylome, we exposed pFFC-Chow mice to an FFC diet in adulthood. These mice developed significant hepatic steatosis, injury, inflammation, and more importantly fibrosis when compared to the appropriate controls. Conclusion: Perinatal exposure to an OID primes the immature liver for an accentuated fibrosing nonalcoholic steatohepatitis (NASH) phenotype, likely through nutritional reprogramming of the offspring methylome. These data have potential clinical implications for monitoring children of obese mothers and risk stratification of children with NAFLD.
Related Concept Videos
02:11The Roles of Bacteria and Fungi in Plant Nutrition
02:40The Eukaryotic Promoter Region
02:40The Eukaryotic Promoter Region
01:27Parentral Nutrition: Centeral and Peripheral Parental Nutrition
PN can be administered through two primary routes:
1. Central Parenteral Nutrition (CPN):
CPN involves delivering a high concentration of nutrients through a large vein. This is typically achieved using a Peripherally Inserted Central Catheter (PICC) or,...
01:28Microbial Nutrition
02:35Key Elements for Plant Nutrition