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Research in Lipid Sciences
Dr. Liqing Yu

Liqing Yu, MD PhD

Assistant Professor of Pathology (Lipid Sciences)
Tel: (336) 716-0920
Fax: (336) 716-6279
lyu@wfubmc.edu

Education:
  • Undergraduate: Hubei Medical University at Xianning, China, MD, 1985
  • Postgraduate: The Third Military Medical University, China, MS in Pathology 1988; Chinese Academy of Medical Sciences & Peking Union Medical University, China, PhD 1995
  • Fellowships: University of Alberta, Canada, 1996-98; University of Texas Southwestern Medical Center at Dallas, 1998-2000
Interests:
  • Teaching: Cell Biology, Gene-Targeting and Transgenics, Molecular Pathobiology 
  • Research: Sterol Trafficking, Triglyceride Metabolism, Metabolic Diseases 
Current Research:

Project 1: NPC1L1 and Metabolic Diseases

 

Niemann-Pick C1-Like 1 (NPC1L1) protein is essential for cholesterol absorption from the gut lumen, a major pathway governing whole-body cholesterol homeostasis. It is the molecular target of a potent cholesterol-lowering drug ezetimibe (commercially known as Zetia). Unexpectedly, we and others found that mice lacking NPC1L1 or treated with ezetimibe are completely protected against high fat diet-induced obesity and fatty liver. We are currently probing how NPC1L1-dependent intestinal cholesterol absorption and ezetimibe modulate the pathogenesis of metabolic diseases such as obesity, fatty liver, and type 2 diabetes by using several genetically engineered mouse models and biochemical approaches.

 

Project 2: CGI-58 and Metabolic Diseases

 

Dysregulation of lipid metabolism is a hallmark of metabolic diseases such as fatty liver, obesity and diabetes, which contribute substantially to disease morbidity and mortality. A gene implicated in cellular fat balance is CGI-58 (Comparative Gene Identification-58), a lipid droplet-associated protein that is also known as abhd5 (a/b-hydrolase domain-containing 5). Mutations in human CGI-58 cause a neutral lipid storage disease, Chanarin-Dorfman syndrome that presents with ichthyosis (thickened dry skin) and accumulation of triglyceride-rich lipid droplets in most tissues. CGI-58 is ubiquitously expressed. CGI-58 appears to function as a coactivator of a triglyceride hydrolase in vitro. We found that CGI-58-driven triglyceride hydrolysis augments fatty acid oxidation and lipoprotein-lipid secretion in cultured hepatoma cells. CGI-58 may have similar functions in vivo. Interestingly, we observed that inhibition of CGI-58 in mice by antisense oligonucleotides causes severe fatty liver, but paradoxically and dramatically increases insulin sensitivity. Since whole-body CGI-58 knockout mice die shortly after birth due to a skin barrier defect, we have created CGI-58 floxed mice using the gene-targeting technology. After crossing with tissue-specific or inducible Cre enzyme-expressing mice, CGI-58 gene can be selectively deleted in a tissue-specific or inducible manner. We are currently using these animals to explore tissue-specific roles of CGI-58 in fat metabolism, insulin signaling, and inflammatory signaling.

 

Recent Publications:

Temel RE, Brown JM, Ma Y, Tang W, Rudel LL, Ioannou YA, Davies JP, Yu L. Diosgenin stimulation of fecal cholesterol excretion in mice is not NPC1L1-dependent. J Lipid Res. 2009 May;50(5):915-23.

Tang W, Ma Y, Jia L, Ioannou YA, Davies JP, Yu L. Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8. J Lipid Res. 2009 Feb;50(2):293-300.

Petersen NH, Faegeman NJ, Yu L, Wüstner D. Kinetic imaging of NPC1L1 and sterol trafficking between plasma membrane and recycling endosomes in hepatoma cells. J Lipid Res. 2008 Sep;49(9):2023-37.

Yu L.  The structure and function of Niemann-Pick C1-like 1 protein. Curr Opin Lipidol. 2008 Jun;19(3):263-9. Review. Erratum in: Curr Opin Lipidol. 2008 Aug;19(4):440.

Tang W, Ma Y, Jia L, Ioannou YA, Davies JP, Yu L. Niemann-Pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):448-54.

Brown JM, Rudel LL, Yu L.  NPC1L1 (Niemann-Pick C1-like 1) mediates sterol-specific unidirectional transport of non-esterified cholesterol in McArdle-RH7777 hepatoma cells. Biochem J. 2007 Sep 1;406(2):273-83.

Brown JM, Chung S, Das A, Shelness GS, Rudel LL, Yu L. CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells. J Lipid Res. 2007 Oct;48(10):2295-305.

Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, Davies JP, Nilsson LM, Yu L. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007 Jul;117(7):1968-78.

Tang W, Ma Y, Yu L. Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice. Hepatology. 2006 Nov;44(5):1259-66.

Yu L, Bharadwaj S, Brown JM, Ma Y, Du W, Davis MA, Michaely P, Liu P, Willingham MC, Rudel LL.  Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake. J Biol Chem. 2006 Mar 10;281(10):6616-24.

Langheim S, Yu L, von Bergmann K, Lutjohann D, Xu F, Hobbs HH, Cohen JC. ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile. J Lipid Res. 2005 Aug;46(8):1732-8.

Yu L, von Bergmann K, Lutjohann D, Hobbs HH, Cohen JC. Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8. J Lipid Res. 2005 Aug;46(8):1739-44.

Yu L, Gupta S, Xu F, Liverman AD, Moschetta A, Mangelsdorf DJ, Repa JJ, Hobbs HH, Cohen JC. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2005 Mar 11;280(10):8742-7.

Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen JC, Hobbs HH. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2326-32.

Yang C, Yu L, Li W, Xu F, Cohen JC, Hobbs HH. Disruption of cholesterol homeostasis by plant sterols. J Clin Invest. 2004 Sep;114(6):813-22.

Wilund KR, Yu L, Xu F, Hobbs HH, Cohen JC. High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr-/- mice. J Lipid Res. 2004 Aug;45(8):1429-36.

Yu L, Cao G, Repa J, Stangl H. Sterol regulation of scavenger receptor class B type I in macrophages. J Lipid Res. 2004 May;45(5):889-99.

Yu L, von Bergmann K, Lutjohann D, Hobbs HH, Cohen JC. Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J Lipid Res. 2004 Feb;45(2):301-7.

Graf GA, Yu L, Li WP, Gerard R, Tuma PL, Cohen JC, Hobbs HH. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem. 2003 Nov 28;278(48):48275-82.

Yu M, Gu SM, Zhou L, Zhao GF, Yu LQ, Zhang H, She MP. [Molecular basis of preventive effect of human apolipoprotein-1 on murine vascular smooth muscle cell proliferation and lipid deposition induced by oxidized low density lipoprotein. Zhonghua Yi Xue Za Zhi]. Natl Med J China 2003 Mar 25;83(6):494-7. Chinese.

Yu L, York J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem 2003 May 2;278(18):15565-15570.

Hobbs HH, Graf GA, Yu L, Wilund KR, Cohen JC. Genetic defenses against hypercholesterolemia. Cold Spring Harb Symp Quant Biol. 2002;67:499-505. Review.

Stangl H, Graf GA, Yu L, Cao G, Wyne K. Effect of estrogen on scavenger receptor BI expression in the rat. J Endocrinol. 2002 Dec;175(3):663-72.

Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16237-42.

Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002 Sep;110(5):671-80.

Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000 Dec 1;290(5497):1771-5.

She M, Li H, Yu L, Gu S, Wang Z. Inhibition of intimal lipid deposition in human apolipoprotein A1 transgenic mice. Clin Exp Pharmacol Physiol. 1999 Oct;26(10):833-4.

Walkey CJ, Yu L, Agellon LB, Vance DE. Biochemical and evolutionary significance of phospholipid methylation. J Biol Chem. 1998 Oct 16;273(42):27043-6.

She MP, Yu L. Advances in the pathogenesis of atherosclerosis. Chinese Med J. 1997; 110: 14-21. [Review] [58 refs].

Yu L, She MP. Serum amyloid protein A - a new kind of apolipoproteins: ApoSAA. Chinese J Pathol. 1995; 24: 113-115.

Yu L, Qiu YF. Effects of butyric acid on the growth, cell cycle, and morphology of human lung cancer cells. Acta Acad Med Militaris Tertiae 1991;13: 5-10.

Qiu YF, Yu L. Quantitative analysis of butyric acid-induced nuclear ultrastructural alterations in cells of human lung giant cell carcinoma in vitro. J Med Coll. 1991; PLA 6: 166-169.