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Cellular cholesterol transport and its regulation by fatty acids and phytosterols

Young-Ki Park, University of Nebraska - Lincoln

Abstract

This study focused on sterol transporters and transcription factors involved in cholesterol absorption and efflux to provide a better understanding of cholesterol homeostasis. We investigated the modulation of the cholesterol transporters, including ATP-binding cassette transporter A1 (ABCA1), ABCG1 and scavenger receptor class B, type I (SR-BI), by inflammatory stimuli such as lipopolysaccharide (LPS), tumor necrosis factor α (TNFα) or interleukin-1β (IL-1β) in RAW 264.7 macrophages and peritoneal macrophages elicited from C57BL/6J mice. LPS treatment significantly reduced the expression of ABCG1, but not ABCA1, with a concomitant decrease in peroxisome proliferator activated receptor γ (PPARγ) expression. Cholesterol efflux to high-density lipoprotein 2 (HDL2) was significantly decreased by LPS. Rosiglitazone, a PPARγ agonist treatment showed a 3-fold increase in ABCG1 mRNA whereas ABCA1 and liver X receptor α (LXRα) expression was not altered. Consistent with RAW 264.7 macrophages, LPS, TNFα, or IL-1β significantly reduced ABCG1 and PPARγ in elicited mouse peritoneal macrophages and ABCG1 protein was also decreased by LPS. The data suggested that 1) LXR-independent ABCA1 expression in macrophages is increased by inflammatory stimulants and 2) ABCG1 expression in macrophages is, at least partly, PPARγ and LXR dependent, which is inhibited by inflammatory stimulants.^ We tested the hypothesis that various fatty acids and phytosterols commonly found in the food supply can modulate the expression of transporters including Niemann-Pick C1-Like 1 (NPC1L1) and SR-BI in intestine and liver cell lines. Cells were treated with 100 μmol/L of a fatty acid for 18 hr and/or 10 μmol/L of 25α-hydroxycholesterol or 100 μmol/L of cholesterol, sitosterol and stigmasterol for 24 hr to measure genes involved in cholesterol transport. Polyunsaturated fatty acids and sterols significantly reduced the mRNA expression levels of NPC1L1, SR-BI, LDLR and HMGR. Importantly, sitosterol and stigmasterol reduced the mRNA levels of the genes to an extent to cholesterol. The data supported the hypothesis that unsaturated fatty acid and phytosterols can alter the expression of genes involved in cholesterol metabolism and transport by functioning as a signaling molecule.^

Subject Area

Health Sciences, Nutrition

Recommended Citation

Park, Young-Ki, "Cellular cholesterol transport and its regulation by fatty acids and phytosterols" (2010). ETD collection for University of Nebraska - Lincoln. AAI3428147.
http://digitalcommons.unl.edu/dissertations/AAI3428147

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