Ryan Temel, Ph.D.

Bio / Education: 
  • Allegheny College, Meadville, PA, B.S., Chemistry, 1995
  • State University of NY at Stony Brook, Stony Brook, NY, Ph.D., Biochemistry & Molecular Biology, 2001
  • Wake Forest University, Winston-Salem, NC, Postdoc, Pathology/Lipid Sciences, 2001-2006
Research Description: 

Role of Hepatic Lipoproteins in Transintestinal Cholesterol Efflux
Excess cholesterol is eliminated from the body by excretion in the feces. It is widely believed that the majority of fecal cholesterol is derived from bile secreted by the liver. However, there is mounting evidence that the liver may also create lipoproteins that can traffic excess cholesterol through the plasma to the small intestine. Through a process known as transintestinal cholesterol efflux (TICE), lipoprotein-associated cholesterol is internalized by the enterocytes and secreted into the lumen of the small intestine. The liver produces two different lipoproteins, high density lipoprotein (HDL) and very low density lipoprotein (VLDL), and based upon our and other groups’ data we hypothesize that VLDL or a by-product of VLDL such as LDL is responsible for funneling cholesterol into the TICE pathway. Our lab will be addressing this hypothesis by genetically manipulating the hepatic expression of genes involved HDL and VLDL production in wild type mice and NPC1L1 liver transgenic mice, which appear to excrete cholesterol primarily via TICE.

Effects of Anti-miR-33 on Atherosclerosis Regression and Reverse Cholesterol Transport
The risk of coronary heart disease (CHD), the largest major killer of Americans, is inversely associated with high-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to the role of HDL in reverse cholesterol transport (RCT), a process whereby cholesterol from macrophage foam cells in atherosclerotic plaques is effluxed to HDL, transported to the liver, and excreted in the feces. Despite intense efforts to identify new therapeutic strategies to raise HDL, this has proven to be a challenging endeavor. A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans, two isoforms of this microRNA, miR-33a and miR-33b, are encoded in introns of the sterol response element binding factor (SREBF) 2 and SREBF1 genes, and co-regulate cellular lipid homeostasis with their host genes. Notably, miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterol efflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1 (ABCA1), a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice, which encode only miR-33a, an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic and macrophage ABCA1, HDL-C, RCT, and atherosclerosis regression. However the translational value of the studies in mice was limited by the lack of miR-33b, which is expressed in humans and non-humans primates. To test the effects of inhibiting both miR-33a and b, we recently treated African green monkeys with anti-miR- 33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceride was decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33, the ability of anti-miR-33 to induce the regression of atherosclerosis in a “human-like” species expressing both miR-33a and miR-33b is still unknown. Our lab proposes to determine the effects of anti-miR-33 on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD.

Grants: 

Title: Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
PI: Ryan E. Temel
Agency: NIH, NHLBI
Goal of Project: Determine whether miR-33 antagonism can stimulate atherosclerosis regression and reverse cholesterol transport in nonhuman primates.

Selected Publications: 

Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Temel RE, Sawyer JK, Yu L, Lord C, Degirolamo C, McDaniel A, Marshall S, Wang N, Shah R, Rudel LL, Brown JM. Cell Metab. 2010;12:96-102. PMCID: PMC2913877

Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE*, Moore KJ. Nature. 2011;478:404-7. PMCID: PMC3235584 (* co-contributing author)

Intestinal SR-BI Does Not Impact Cholesterol Absorption or Transintestinal Cholesterol Efflux (TICE) in Mice. Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK, Shah R, Wilson MD, Dikkers A, Tietge UJ, Collet X, Rudel LL, Temel RE*, Brown JM. J Lipid Res. 2013;54:1567-77. (* co-contributing author)

PubMed Publications: 

  • Medina, M.W.;Bauzon, F.;Naidoo, D.;Theusch, E.;Stevens, K.;Schilde, J.;Schubert, C.;Mangravite, L.M.;Rudel, L.L.;Temel, R.E.;Runz, H.;Krauss, R.M. "Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism." Arteriosclerosis, thrombosis, and vascular biology 34, 9 (2014): 1917-23. [PubMed Link] | [ Full text ]
  • Hung, S.C.;Cuffe, H.;Marshall, S.M.;McDaniel, A.L.;Ha, J.H.;Kavanagh, K.;Hong, C.;Tontonoz, P.;Temel, R.E.;Parks, J.S. "Dietary cholesterol promotes adipocyte hypertrophy and adipose tissue inflammation in visceral, but not in subcutaneous, fat in monkeys." Arteriosclerosis, thrombosis, and vascular biology 34, 9 (2014): 1880-7. [PubMed Link] | [ Full text ]
  • Zhang, H.;Temel, R.E.;Martel, C. "Cholesterol and lipoprotein metabolism: Early Career Committee contribution." Arteriosclerosis, thrombosis, and vascular biology 34, 9 (2014): 1791-4. [PubMed Link] | [ Full text ]
  • Hong, C.;Marshall, S.M.;McDaniel, A.L.;Graham, M.;Layne, J.D.;Cai, L.;Scotti, E.;Boyadjian, R.;Kim, J.;Chamberlain, B.T.;Tangirala, R.K.;Jung, M.E.;Fong, L.;Lee, R.;Young, S.G.;Temel, R.E.;Tontonoz, P. "The LXR-Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice." Cell metabolism 20, 5 (2014): 910-8. [PubMed Link] | [ Full text ]
  • Marshall, S.M.;Kelley, K.L.;Davis, M.A.;Wilson, M.D.;McDaniel, A.L.;Lee, R.G.;Crooke, R.M.;Graham, M.J.;Rudel, L.L.;Brown, J.M.;Temel, R.E. "Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice." PloS one 9, 1 (2014): e84418. [PubMed Link] | [ Full text ]
  • Marshall, S.M.;Gromovsky, A.D.;Kelley, K.L.;Davis, M.A.;Wilson, M.D.;Lee, R.G.;Crooke, R.M.;Graham, M.J.;Rudel, L.L.;Brown, J.M.;Temel, R.E. "Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion." PloS one 9, 6 (2014): e98953. [PubMed Link] | [ Full text ]
  • Beason, D.P.;Hsu, J.E.;Marshall, S.M.;McDaniel, A.L.;Temel, R.E.;Abboud, J.A.;Soslowsky, L.J. "Hypercholesterolemia increases supraspinatus tendon stiffness and elastic modulus across multiple species." Journal of shoulder and elbow surgery / American Shoulder and Elbow Surgeons ... [et al.] 22, 5 (2013): 681-6. [PubMed Link] | [ Full text ]
  • Bura, K.S.;Lord, C.;Marshall, S.;McDaniel, A.;Thomas, G.;Warrier, M.;Zhang, J.;Davis, M.A.;Sawyer, J.K.;Shah, R.;Wilson, M.D.;Dikkers, A.;Tietge, U.J.;Collet, X.;Rudel, L.L.;Temel, R.E.;Brown, J.M. "Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice." Journal of lipid research 54, 6 (2013): 1567-77. [PubMed Link] | [ Full text ]
  • Saddar, S.;Carriere, V.;Lee, W.R.;Tanigaki, K.;Yuhanna, I.S.;Parathath, S.;Morel, E.;Warrier, M.;Sawyer, J.K.;Gerard, R.D.;Temel, R.E.;Brown, J.M.;Connelly, M.;Mineo, C.;Shaul, P.W. "Scavenger receptor class B type I is a plasma membrane cholesterol sensor." Circulation research 112, 1 (2013): 140-51. [PubMed Link] | [ Full text ]
  • McDaniel, A.L.;Alger, H.M.;Sawyer, J.K.;Kelley, K.L.;Kock, N.D.;Brown, J.M.;Temel, R.E.;Rudel, L.L. "Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice." The American journal of pathology 182, 4 (2013): 1131-8. [PubMed Link] |
  • Owens AP, 3rd;Passam, F.H.;Antoniak, S.;Marshall, S.M.;McDaniel, A.L.;Rudel, L.;Williams, J.C.;Hubbard, B.K.;Dutton, J.A.;Wang, J.;Tobias, P.S.;Curtiss, L.K.;Daugherty, A.;Kirchhofer, D.;Luyendyk, J.P.;Moriarty, P.M.;Nagarajan, S.;Furie, B.C.;Furie, B.;Johns, D.G.;Temel, R.E.;Mackman, N. "Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin." The Journal of clinical investigation 122, 2 (2012): 558-68. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Brown, J.M. "Biliary and nonbiliary contributions to reverse cholesterol transport." Current opinion in lipidology 23, 2 (2012): 85-90. [PubMed Link] | [ Full text ]
  • Rayner, K.J.;Esau, C.C.;Hussain, F.N.;McDaniel, A.L.;Marshall, S.M.;Gils, J.M.;Ray, T.D.;Sheedy, F.J.;Goedeke, L.;Liu, X.;Khatsenko, O.G.;Kaimal, V.;Lees, C.J.;Fernandez-Hernando, C.;Fisher, E.A.;Temel, R.E.;Moore, K.J. "Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides." Nature 478, 7369 (2011): 404-7. [PubMed Link] | [ Full text ]
  • Rayner, K.J.;Sheedy, F.J.;Esau, C.C.;Hussain, F.N.;Temel, R.E.;Parathath, S.;Gils, J.M.;Rayner, A.J.;Chang, A.N.;Suarez, Y.;Fernandez-Hernando, C.;Fisher, E.A.;Moore, K.J. "Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis." The Journal of clinical investigation 121, 7 (2011): 2921-31. [PubMed Link] | [ Full text ]
  • Medina, M.W.;Gao, F.;Naidoo, D.;Rudel, L.L.;Temel, R.E.;McDaniel, A.L.;Marshall, S.M.;Krauss, R.M. "Coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake." PloS one 6, 4 (2011): e19420. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Sawyer, J.K.;Yu, L.;Lord, C.;Degirolamo, C.;McDaniel, A.;Marshall, S.;Wang, N.;Shah, R.;Rudel, L.L.;Brown, J.M. "Biliary sterol secretion is not required for macrophage reverse cholesterol transport." Cell metabolism 12, 1 (2010): 96-102. [PubMed Link] |
  • Temel, R.E.;Brown, J.M. "A new framework for reverse cholesterol transport: non-biliary contributions to reverse cholesterol transport." World journal of gastroenterology : WJG 16, 47 (2010): 5946-52. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Brown, J.M.;Ma, Y.;Tang, W.;Rudel, L.L.;Ioannou, Y.A.;Davies, J.P.;Yu, L. "Diosgenin stimulation of fecal cholesterol excretion in mice is not NPC1L1 dependent." Journal of lipid research 50, 5 (2009): 915-23. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Rudel, L.L. "Diet effects on atherosclerosis in mice." Current drug targets 8, 11 (2007): 1150-60. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Tang, W.;Ma, Y.;Rudel, L.L.;Willingham, M.C.;Ioannou, Y.A.;Davies, J.P.;Nilsson, L.M.;Yu, L. "Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe." The Journal of clinical investigation 117, 7 (2007): 1968-78. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Hou, L.;Rudel, L.L.;Shelness, G.S. "ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins." Journal of lipid research 48, 7 (2007): 1618-27. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Lee, R.G.;Kelley, K.L.;Davis, M.A.;Shah, R.;Sawyer, J.K.;Wilson, M.D.;Rudel, L.L. "Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2." Journal of lipid research 46, 11 (2005): 2423-31. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Gebre, A.K.;Parks, J.S.;Rudel, L.L. "Compared with Acyl-CoA:cholesterol O-acyltransferase (ACAT) 1 and lecithin:cholesterol acyltransferase, ACAT2 displays the greatest capacity to differentiate cholesterol from sitosterol." The Journal of biological chemistry 278, 48 (2003): 47594-601. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Parks, J.S.;Williams, D.L. "Enhancement of scavenger receptor class B type I-mediated selective cholesteryl ester uptake from apoA-I(-/-) high density lipoprotein (HDL) by apolipoprotein A-I requires HDL reorganization by lecithin cholesterol acyltransferase." The Journal of biological chemistry 278, 7 (2003): 4792-9. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Walzem, R.L.;Banka, C.L.;Williams, D.L. "Apolipoprotein A-I is necessary for the in vivo formation of high density lipoprotein competent for scavenger receptor BI-mediated cholesteryl ester-selective uptake." The Journal of biological chemistry 277, 29 (2002): 26565-72. [PubMed Link] | [ Full text ]
  • Williams, D.L.;Temel, R.E.;Connelly, M.A. "Roles of scavenger receptor BI and APO A-I in selective uptake of HDL cholesterol by adrenal cells." Endocrine research 26, 4 (2000): 639-51. [PubMed Link] |
  • Swarnakar, S.;Temel, R.E.;Connelly, M.A.;Azhar, S.;Williams, D.L. "Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester." The Journal of biological chemistry 274, 42 (1999): 29733-9. [PubMed Link] | [ Full text ]
  • Rodrigueza, W.V.;Thuahnai, S.T.;Temel, R.E.;Lund-Katz, S.;Phillips, M.C.;Williams, D.L. "Mechanism of scavenger receptor class B type I-mediated selective uptake of cholesteryl esters from high density lipoprotein to adrenal cells." The Journal of biological chemistry 274, 29 (1999): 20344-50. [PubMed Link] | [ Full text ]
  • Williams, D.L.;Connelly, M.A.;Temel, R.E.;Swarnakar, S.;Phillips, M.C.;Llera-Moya, M.;Rothblat, G.H. "Scavenger receptor BI and cholesterol trafficking." Current opinion in lipidology 10, 4 (1999): 329-39. [PubMed Link] | [ Full text ]
  • Temel, R.E.;Trigatti, B.;DeMattos, R.B.;Azhar, S.;Krieger, M.;Williams, D.L. "Scavenger receptor class B, type I (SR-BI) is the major route for the delivery of high density lipoprotein cholesterol to the steroidogenic pathway in cultured mouse adrenocortical cells." Proceedings of the National Academy of Sciences of the United States of America 94, 25 (1997): 13600-5. [PubMed Link] | [ Full text ]
  • Serra, M.J.;Barnes, T.W.;Betschart, K.;Gutierrez, M.J.;Sprouse, K.J.;Riley, C.K.;Stewart, L.;Temel, R.E. "Improved parameters for the prediction of RNA hairpin stability." Biochemistry 36, 16 (1997): 4844-51. [PubMed Link] | [ Full text ]
  • Rigotti, A.;Edelman, E.R.;Seifert, P.;Iqbal, S.N.;DeMattos, R.B.;Temel, R.E.;Krieger, M.;Williams, D.L. "Regulation by adrenocorticotropic hormone of the in vivo expression of scavenger receptor class B type I (SR-BI), a high density lipoprotein receptor, in steroidogenic cells of the murine adrenal gland." The Journal of biological chemistry 271, 52 (1996): 33545-9. [PubMed Link] | [ Full text ]
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