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Maternal Western diet is associated with distinct preclinical pediatric NAFLD phenotypes in juvenile nonhuman primate
Michael J Nash1, Evgenia Dobrinskikh1, Rachel C Janssen2
1Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Insights
Maternal Western-style diet (mWSD) in nonhuman primates causes liver changes in offspring. Postweaning diet (pwWSD) exacerbates these effects, increasing fibrosis and endoplasmic reticulum stress, preceding clinical nonalcoholic fatty liver disease (NAFLD).
Area of Science:
- Hepatology and Nutritional Science
- Developmental Biology
- Metabolomics and Transcriptomics
Background:
- Pediatric nonalcoholic fatty liver disease (NAFLD) has unclear causation, despite distinct pathology.
- Maternal Western-style diet (mWSD) in nonhuman primates induces hepatic injury and steatosis in fetal offspring.
- Understanding the long-term molecular impact of maternal and postweaning diet is crucial for pediatric NAFLD research.
Purpose of the Study:
- To define the role of maternal Western-style diet (mWSD) and postweaning Western-style diet (pwWSD) on molecular mechanisms of NAFLD development.
- To investigate hepatic pathways regulating NAFLD in juvenile nonhuman primates exposed to different dietary regimens.
- To identify persistent molecular alterations associated with early-life diet exposure preceding clinical NAFLD.
Main Methods:
- Histologic, transcriptomic, and metabolomic analyses were employed in 3-year-old juvenile nonhuman primates.
- Offspring were exposed to either maternal chow diet (CD) or mWSD, followed by CD or pwWSD.
- Gene expression, protein levels, and metabolite profiles were assessed to identify NAFLD-related pathways.
Main Results:
- Maternal Western-style diet (mWSD) exposure led to increased hepatic periportal collagen deposition and altered gene expression pathways (e.g., HNF4α, antioxidant signaling, PPAR signaling).
- Postweaning Western-style diet (pwWSD) exposure, especially combined with mWSD, upregulated fibrosis and endoplasmic reticulum stress pathways, increased specific acylcarnitines, and decreased anti-inflammatory fatty acids.
- mWSD shifted liver metabolites towards decreased purine catabolism, suggesting a mitochondrial DNA repair response, while pwWSD exacerbated oxidative stress and compromised lipid sensing.
Conclusions:
- Maternal Western-style diet (mWSD) exposure in nonhuman primates induces persistent hepatic changes in juvenile offspring, including collagen deposition and altered metabolic/transcriptional pathways indicative of oxidative stress and compromised mitochondrial function.
- Postweaning Western-style diet (pwWSD) exposure significantly worsens these phenotypes, promoting fibrosis and endoplasmic reticulum stress.
- These findings highlight the critical role of early-life nutrition in NAFLD pathogenesis and suggest that dietary interventions are crucial even before clinical NAFLD presentation.
Abstract:
Pediatric NAFLD has distinct and variable pathology, yet causation remains unclear. We have shown that maternal Western-style diet (mWSD) compared with maternal chow diet (CD) consumption in nonhuman primates produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning Western-style diet (pwWSD) exposures on molecular mechanisms linked to NAFLD development in a cohort of 3-year-old juvenile nonhuman primates offspring exposed to maternal CD or mWSD followed by CD or Western-style diet after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic periportal collagen deposition but unchanged hepatic triglyceride levels and body weight. mWSD was associated with a downregulation of gene expression pathways underlying HNF4α activity and protein, and downregulation of antioxidant signaling, mitochondrial biogenesis, and PPAR signaling pathways. In offspring exposed to both mWSD and pwWSD, liver RNA profiles showed upregulation of pathways promoting fibrosis and endoplasmic reticulum stress and increased BiP protein expression with pwWSD. pwWSD increased acylcarnitines and decreased anti-inflammatory fatty acids, which was more pronounced when coupled with mWSD exposure. Further, mWSD shifted liver metabolites towards decreased purine catabolism in favor of synthesis, suggesting a mitochondrial DNA repair response. Our findings demonstrate that 3-year-old offspring exposed to mWSD but weaned to a CD have periportal collagen deposition, with transcriptional and metabolic pathways underlying hepatic oxidative stress, compromised mitochondrial lipid sensing, and decreased antioxidant response. Exposure to pwWSD worsens these phenotypes, triggers endoplasmic reticulum stress, and increases fibrosis. Overall, mWSD exposure is associated with altered expression of candidate genes and metabolites related to NAFLD that persist in juvenile offspring preceding clinical presentation of NAFLD.
