Linoleic Acid: Associations with Bone Health Among Women Living with HIV and Effects on Osteoblast Metabolism Restricted; Files Only
Nesbeth, Paula-Dene (Spring 2024)
Abstract
Osteoporosis is a serious bone disease characterized by severe bone loss, deteriorated bone microarchitecture, and increased risk of debilitating fractures. Postmenopausal women and people living with human immunodeficiency virus (HIV) infection, are at risk for osteoporosis. Over the adult lifespan, bone is homeostatically remodeled through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Factors that disrupt this remodeling process lead to bone loss and osteoporosis.
Polyunsaturated fatty acids (PUFA) are major dietary constituents involved in numerous cell functions, including as precursors to oxylipins which are potent lipid mediators active in both bone homeostasis and inflammation. The n-6 PUFA linoleic acid (LNA) is an essential fatty acid and the most consumed PUFA in the US diet. The role of LNA on bone health is controversial.
This dissertation utilizes clinical and molecular studies to determine the relationships between PUFA, PUFA metabolism, and bone health indicators. For Aim 1, we conducted cross-sectional high-resolution plasma metabolomics analyses to identify metabolites and metabolic pathways associated with bone mineral density (BMD) Z-scores and serum bone turnover markers (BTM), in women living with HIV (WLH) and at-risk women who are HIV-negative. The association of plasma PUFA concentrations with Z-scores and serum BTM were determined in these study participants (Aim 2). For Aim 3, we investigated the effects of LNA on osteoblast differentiation, gene expression, and energy metabolism in mouse osteoblast precursor cells.
Results indicated that: 1) lumbar spine Z-score was positively associated with metabolites enriched within n-6 PUFA metabolism in WLH; 2) however, individual plasma PUFA concentrations were not associated with either Z-scores (femoral neck, lumbar spine, and total hip) or serum BTM; and 3) LNA treatment in osteoblast precursor cells inhibited early differentiation, mitochondrial energy production, and increased intracellular concentrations of oxylipins derived from LNA and another n-6 PUFA, arachidonic acid (ARA). Plasma LNA and other PUFA were not related to indicators of bone health; however, possible effects may be mediated by their oxylipin derivates. LNA appears to play a role in bone health and metabolism.
Table of Contents
CHAPTER 1 Introduction and Background............................................................. 1
Osteoporosis............................................................................................................... 1
Health conditions and diseases affecting the skeleton............................................... 3
Nutrition and bone health........................................................................................... 6
Specific research aims.............................................................................................. 11
Chapter 1 References............................................................................................... 14
CHAPTER 2 Extended Methods.............................................................................. 22
Chapter Overview.................................................................................................... 22
Extended Methods for Chapter 3 and Chapter 4...................................................... 22
Extended Methods for Chapter 5............................................................................. 28
Chapter 2 References............................................................................................... 36
CHAPTER 3 Plasma metabolomic associations with bone mineral density and serum markers of bone turnover in women living with and at risk for HIV....... 45
Abstract.................................................................................................................... 46
Introduction.............................................................................................................. 47
Methods.................................................................................................................... 49
Results...................................................................................................................... 54
Discussion................................................................................................................ 61
Conclusion............................................................................................................... 67
Chapter 3 References............................................................................................... 69
CHAPTER 4 Associations of plasma polyunsaturated fatty acids with bone mineral density and serum markers of bone turnover in women living with or at risk for HIV................................................................................................................ 94
Abstract.................................................................................................................... 95
Introduction.............................................................................................................. 97
Methods.................................................................................................................... 99
Results.................................................................................................................... 103
Discussion.............................................................................................................. 105
Conclusion............................................................................................................. 109
Chapter 4 References............................................................................................. 110
CHAPTER 5 Linoleic acid blunts early osteoblast differentiation and impairs oxidative phosphorylation in vitro.......................................................................... 134
Abstract.................................................................................................................. 135
Introduction............................................................................................................ 136
Materials and Methods........................................................................................... 138
Results.................................................................................................................... 144
Discussion.............................................................................................................. 148
Conclusion............................................................................................................. 154
Funding.................................................................................................................. 154
Acknowledgements................................................................................................ 154
Chapter 5 References............................................................................................. 155
CHAPTER 6 Summary of major contributions from population and molecular analyses: n-6 polyunsaturated fatty acids and modulation of bone homeostasis.................................................................................................................................... 180
Introduction............................................................................................................ 180
Major findings........................................................................................................ 181
Future directions.................................................................................................... 186
Conclusion............................................................................................................. 189
Chapter 6 References............................................................................................. 190
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File download under embargo until 22 May 2025 | 2024-04-03 09:17:42 -0400 | File download under embargo until 22 May 2025 |
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