UC Davis

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.