Lawrence L Rudel

Publications (225) View all

• Article: Intestinal SR-BI Does Not Impact Cholesterol Absorption or Transintestinal Cholesterol Efflux (TICE) in Mice.

  Kanwardeep S Bura, Caleb Lord, Stephanie Marshall, Allison McDaniel, Gwyn Thomas, Manya Warrier, Jun Zhang, Matthew A Davis, Janet K Sawyer, Ramesh Shah, Martha D Wilson, Arne Dikkers, Uwe J F Tietge, Xavier Collet, Lawrence L Rudel, Ryan E Temel, J Mark Brown
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  ABSTRACT: Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the non-biliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI in TICE has not been studied. To examine the role of intestinal SR-BI in TICE, sterol balance was measured in control mice and mice transgenically overexpressing SR-BI in the proximal small intestine (SR-BIhApoCIII-ApoAIV-Tg). SR-BIhApoCIII-ApoAIV-Tg mice had significantly lower plasma cholesterol levels compared to WT controls, yet SR-BIhApoCIII-ApoAIV-Tg mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. To specifically study effects of intestinal SR-BI on TICE we crossed SR-BIhApoCIII-ApoAIV-Tg mice into a mouse model that preferentially utilizes the TICE pathway for RCT (NPC1L1LiverTg), and likewise found no alterations in cholesterol absorption or fecal sterol excretion. Finally, mice lacking SR-BI in all tissues also exhibited normal cholesterol absorption and fecal cholesterol disposal. Collectively, these results suggest that SR-BI is not rate-limiting for intestinal cholesterol absorption or for fecal neutral sterol loss through the TICE pathway.
  The Journal of Lipid Research 04/2013; · 5.56 Impact Factor
• Article: Phytosterol Feeding Causes Toxicity in ABCG5/G8 Knockout Mice.

  Allison L McDaniel, Heather M Alger, Janet K Sawyer, Kathryn L Kelley, Nancy D Kock, J Mark Brown, Ryan E Temel, Lawrence L Rudel
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  ABSTRACT: Plant sterols, or phytosterols, are very similar in structure to cholesterol and are abundant in typical diets. The reason for poor absorption of plant sterols by the body is still unknown. Mutations in the ABC transporters G5 and G8 are known to cause an accumulation of plant sterols in blood and tissues (sitosterolemia). To determine the significance of phytosterol exclusion from the body, we fed wild-type and ABCG5/G8 knockout mice a diet enriched with plant sterols. The high-phytosterol diet was extremely toxic to the ABCG5/G8 knockout mice but had no adverse effects on wild-type mice. ABCG5/G8 knockout mice died prematurely and developed a phenotype that included high levels of plant sterols in many tissues, liver abnormalities, and severe cardiac lesions. This study is the first to report such toxic effects of phytosterol accumulation in ABCG5/G8 knockout mice. We believe these new data support the conclusion that plant sterols are excluded from the body because they are toxic when present at high levels.
  American Journal Of Pathology 02/2013; · 4.89 Impact Factor
• Article: Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: Part 1.

  Masaki Ohtawa, Hiroyuki Yamazaki, Satoshi Ohte, Daisuke Matsuda, Taichi Ohshiro, Lawrence L Rudel, Satoshi Omura, Hiroshi Tomoda, Tohru Nagamitsu
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  ABSTRACT: In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). We have successfully developed novel PPPA derivatives with a 7-O-substituted benzoyl substituent that significantly exhibit more potent ACAT2 inhibitory activity and higher ACAT2 isozyme selectivity than 1.
  Bioorganic & medicinal chemistry letters 01/2013; · 2.65 Impact Factor
• Article: ACAT Inhibition Reduces the Progression of Preexisting, Advanced Atherosclerotic Mouse Lesions Without Plaque or Systemic Toxicity.

  James X Rong, Courtney Blachford, Jonathan E Feig, Ilda Bander, Jeffrey Mayne, Jun K Usunoki, Christine Miller, Matthew Davis, Martha Wilson, Shirley Dehn, Edward Thorp, Ira Tabas, Mark B Taubman, Lawrence L Rudel, Edward A Fisher
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  ABSTRACT: OBJECTIVE: Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters in plaque foam cells. Complete deficiency of macrophage ACAT has been shown to increase atherosclerosis in hypercholesterolemic mice because of cytotoxicity from free cholesterol accumulation, whereas we previously showed that partial ACAT inhibition by Fujirebio compound F1394 decreased early atherosclerosis development. In this report, we tested F1394 effects on preestablished, advanced lesions of apolipoprotein-E-deficient mice. METHODS AND RESULTS: Apolipoprotein-E-deficient mice on Western diet for 14 weeks developed advanced plaques, and were either euthanized (Baseline), or continued on Western diet with or without F1394 and euthanized after 14 more weeks. F1394 was not associated with systemic toxicity. Compared with the baseline group, lesion size progressed in both groups; however, F1394 significantly retarded plaque progression and reduced plaque macrophage, free and esterified cholesterol, and tissue factor contents compared with the untreated group. Apoptosis of plaque cells was not increased, consistent with the decrease in lesional free cholesterol, no increase in plaque necrosis, and unimpaired efferocytosis (phagocytic clearance of apoptotic cells). The effects of F1394 were independent of changes in plasma cholesterol levels. CONCLUSIONS: Partial ACAT inhibition by F1394 lowered plaque cholesterol content and had other antiatherogenic effects in advanced lesions in apolipoprotein-E-deficient mice without overt systemic or plaque toxicity, suggesting the continued potential of ACAT inhibition for the clinical treatment of atherosclerosis, in spite of recent trial data.
  Arteriosclerosis Thrombosis and Vascular Biology 11/2012; · 6.37 Impact Factor
• Article: 25(OH)D3 and cardiovascular risk factors in female nonhuman primates.

  Matthew J Jorgensen, Lawrence L Rudel, Matthew Nudy, Jay R Kaplan, Thomas B Clarkson, Nicholas M Pajewski, Peter F Schnatz
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  ABSTRACT: To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (25(OH)D(3)) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C). One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3-25 years consumed a typical western diet for 7-8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D(3). Measurements of vitamin D(3) and HDL-C concentrations, as well as waist circumference, were obtained. Among young monkeys (aged 3-5 years), compared to older monkeys (aged 16-25 years), the mean plasma 25(OH)D(3) concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D(3) concentrations had a range of 19.6-142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ng/mL). 25(OH)D(3) concentrations were inversely associated with age (p<0.0001) and waist circumference (p=0.016) and were positively correlated with HDL-C (p=0.01). However, when statistically controlling for age, none of these relationships remained significant. Conclusions: Higher plasma concentrations of 25(OH)D(3) were associated with more favorable cardiovascular risk factors, with inverse associations observed between 25(OH)D(3) and abdominal obesity, HDL-C, and age. These associations were no longer significant when controlling for age.
  Journal of Women s Health 08/2012; 21(9):959-65. · 1.57 Impact Factor