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Scholarly Works (5 results)

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

High-density lipoproteins (HDL), inflammation pathways, and associated proteins likelipopolysaccharide binding protein (LBP) play complex and interrelated roles in major age- related diseases including cardiovascular disease and Alzheimer’s disease (AD). This dissertation integrates findings across multiple key studies to elucidate novel insights of the “lipoprotein-gastrointestinal-inflammation axis” underlying these conditions. By reviewing evidence on HDL glycoprotein alterations in disease, identifying elevated LBP in Alzheimer’s patients and analyzing impacts of fiber supplementation on inflammation in preliminary trials, new insights emerge. These discoveries pave the way for improved risk prediction, prevention, and treatment strategies that leverage knowledge of HDL, LBP, and glycosylation aberrations. This body of work catalyzes future research to enable transformative advances against society’s most pressing health burdens.

1. Chapter one reviews research on glycosylation of HDL-associated proteins, showing it isaltered in diseases like cardiovascular disease (CVD) and has potential as a diagnostic biomarker. It discusses analytical methods for profiling HDL glycoproteins and evidence linking glycosylation to HDL function. The chapter emphasizes the need for large cohort studies on HDL glycan profiles and health outcomes.

2. Chapter two presents findings from an Alzheimer's study identifying significantly higherLBP concentrations in plasma fractions of apolipoprotein E (APOE)3E3 AD patients compared to APOE3E4 controls. LBP was associated with dementia severity and verbal memory scores. This implicates LBP-driven inflammation in AD pathogenesis in genetically low-risk individuals.

3. Chapter three analyzes data from a prebiotic fiber supplementation trial, finding limitedoverall impacts of the fiber supplement on plasma concentrations of LBP and HDL function, but reductions in LBP selectively in those individuals with higher baseline LBP. Our findings suggest that some individuals who consume low-fiber diets have increased gut permeability, and for these individuals, even a low-dose daily fiber supplement can improve gut barrier function.

Together, these discoveries reveal new aspects of lipoproteins, LBP, and glycosylation in majorage-related disease. This dissertation promotes future research leveraging this knowledge for enhanced prediction, prevention, and treatment of conditions like AD and CVD. Key priorities include large glycoprofiling studies, elucidating LBP's role in AD, and assessing early-life precision nutrition anti-inflammatory interventions in at-risk groups.

    Cover page: Precision Nutrition for the Management and Prevention of Chronic Disease: Exploring the Relationship Between Intestinal Permeability and High-Density Lipoproteins in Alzheimer’s Disease
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2022)
    High-density lipoprotein (HDL) particles, long known for their critical role in the prevention of cardiovascular disease (CVD), were recently identified to carry a wide array of glycosylated proteins, and the importance of this glycosylation in the structure, function and metabolism of HDL are starting to emerge. Early studies have demonstrated differential glycosylation of HDL-associated proteins in various pathological states, which may be key to understanding their etiological role in these diseases and may be important for diagnostic development. Given the vast array and specificity of glycosylation pathways, the study of HDL-associated glycosylation has the potential to uncover novel mechanisms and biomarkers of CVD. To date, no large studies examining the relationships between HDL glycosylation profiles and cardiovascular outcomes have been performed. However, small pilot studies provide promising preliminary evidence that such a relationship may exist. In this review article we discuss the current state of the evidence on the glycosylation of HDL-associated proteins, the potential for HDL glycosylation profiling in CVD diagnostics, how glycosylation affects HDL function, and the potential for modifying the glycosylation of HDL-associated proteins to confer therapeutic value.
      Cover page: Glycosylation of HDL-Associated Proteins and Its Implications in Cardiovascular Disease Diagnosis, Metabolism and Function
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2023)

      Purpose of review

      Emerging evidence supports the promise of precision nutritional approaches for cardiovascular disease (CVD) prevention. Here, we discuss current findings from precision nutrition trials and studies reporting substantial inter-individual variability in responses to diets and dietary components relevant to CVD outcomes. We highlight examples where early precision nutrition research already points to actionable intervention targets tailored to an individual's biology and lifestyle. Finally, we make the case for high-density lipoproteins (HDL) as a compelling next generation target for precision nutrition aimed at CVD prevention. HDL possesses complex structural features including diverse protein components, lipids, size distribution, extensive glycosylation, and interacts with the gut microbiome, all of which influence HDL's anti-inflammatory, antioxidant, and cholesterol efflux properties. Elucidating the nuances of HDL structure and function at an individual level may unlock personalized dietary and lifestyle strategies to optimize HDL-mediated atheroprotection and reduce CVD risk.

      Recent findings

      Recent human studies have demonstrated that HDL particles are key players in the reduction of CVD risk. Our review highlights the role of HDL and the importance of personalized therapeutic approaches to improve their potential for reducing CVD risk. Factors such as diet, genetics, glycosylation, and gut microbiome interactions can modulate HDL structure and function at the individual level. We emphasize that fractionating HDL into size-based subclasses and measuring particle concentration are necessary to understand HDL biology and for developing the next generation of diagnostics and biomarkers. These discoveries underscore the need to move beyond a one-size-fits-all approach to HDL management. Precision nutrition strategies that account for personalized metabolic, genetic, and lifestyle data hold promise for optimizing HDL therapies and function to mitigate CVD risk more potently. While human studies show HDL play a key role in reducing CVD risk, recent findings indicate that factors such as diet, genetics, glycosylation, and gut microbes modulate HDL function at the individual level, underscoring the need for precision nutrition strategies that account for personalized variability to optimize HDL's potential for mitigating CVD risk.
        Cover page: Precision Nutrition and Cardiovascular Disease Risk Reduction: the Promise of High-Density Lipoproteins
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2024)

        Introduction

        The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood.

        Methods

        In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA.

        Results

        LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS).

        Discussion

        These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.
          Cover page: Elevated lipopolysaccharide binding protein in Alzheimer’s disease patients with APOE3/E3 but not APOE3/E4 genotypeCreative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2023)

          Background

          Small-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown.

          Objective

          The goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation.

          Methods

          HDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females.

          Results

          There were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season.

          Conclusions

          Mothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy.

          Clinical trial registry number

          The study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866.
            Cover page: Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana
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