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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2024)

Dietary Influences on Lipid Metabolism: Hepatic and Postprandial Responses to Circulating Triglycerides ABSTRACT Triglycerides (TG) are the primary form of fatty acid storage and transport within cells and plasma. This dissertation aimed to investigate TG metabolism in the context of a polyphenol and high fat meal (HFM) interventions. The first study investigated the effects of flavan-3-ol (-)-epicatechin (EC) on hepatic TG using both in vivo and in vitro models. Male C57BL/6J mice (8 weeks old) were fed either a control diet (10% calories from fat) or the same diet supplemented with 2 or 20 mg EC/kg body weight for 24 weeks. Also, human HepG2 hepatocytes were treated with low and high concentrations (1–10 μM) of EC and its main plasma metabolites. Only the mice receiving the higher amount of EC (20mg/kg body weight) showed elevated hepatic TG content without evidence of hepatic inflammation or oxidative stress. This was accompanied by increased hepatic expression of diacylglycerol acyltransferase 2 (DGAT2), a key TG synthesis enzyme, and PPARα. HepG2 cells treated with high EC concentrations showed no changes in TG accumulation or DGAT2 expression. Overall, findings from the first chapter highlight the safety of EC regarding TG metabolism and liver health if administered in doses rational for humans. As for the second aim of this dissertation, we investigated the extent of plasma TG increments following a HFM and changes in plasma metabolic parameters and global gene expression in peripheral blood mononuclear cells (PBMCs), and how this relates to overall risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). Healthy participants between 18 to 40 years old with a body mass index (BMI) between 21 and 29.9 kg/m2 were given a single HFM, with blood samples collected before and for 5 h post-meal. Plasma (0-5 h) and PBMCs (3 h) were isolated immediately for analysis. Participants were categorized into two groups based on their postprandial plasma TG response with low TG responders (LPTG, <170 mg/dL x 5 h) and high TG responders (HPTG, >700 mg/dL x 5 h). Plasma was analyzed for TG, cholesterol, glucose, insulin, and lipopolysaccharide-binding protein (LBP) concentrations. PBMC mRNA was isolated for genomic and qPCR analysis. HPTG individuals showed exaggerated plasma responses in parameters of lipid and glucose metabolism compared to LPTG individuals. We also observed changes in protein-coding and non-coding RNAs involved in immune response, inflammation, and metabolism. The biochemical and genomic findings suggest that the large postprandial TG increments are linked to potentially greater risk of CVD and T2D. Following up on the previous aim, as for the third chapter, our analysis showed significant sex-dependent differences in postprandial responses. We further investigated these differences in biochemical markers of postprandial dysmetabolism as well as global gene expression in PBMCs. While large increases in postprandial TG responses occurred in both females and males, only male HPTG individuals showed higher postprandial plasma insulin and LBP concentrations compared to LPTG counterparts, suggesting a sex specific effect. In addition, pathway enrichment analysis of KEGG and Wikipathways for both protein-coding and non-coding RNAs showed more differences than similarities between sexes, with males showing a generally higher risk for CVD. The last aim concluded that females and males show distinct metabolic and genomic responses to HFM consumption, potentially influenced by estrogen’s anti-inflammatory effects in females. In conclusion, this dissertation contributes valuable insights into TG metabolism in the context of EC and HFM. Findings indicate that while consuming EC-rich foods appears to be safe, caution is necessary regarding long-term and high-dose EC supplementation until further clinical evidence is available. Also, individuals with normal or mildly elevated fasting TG levels but large postprandial responses, particularly males, may face a higher risk for CVD.

    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2021)
    INTRODUCTION: Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice. RESEARCH DESIGN AND METHODS: We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT2 Profiler PCR array. RESULTS: Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition. CONCLUSION: E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.
      Cover page: Antidiabetic E4orf1 protein prevents hepatic steatosis and reduces markers of aging-related cellular damage in high fat fed older mice.Creative Commons 'BY-NC' version 4.0 license
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2020)
      Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.
        Cover page: (−)-Epicatechin and the comorbidities of obesity
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