Niemann-Pick C1-Like 1 (NPC1L1) was originally identified as an essential protein for intestinal cholesterol absorption. It is the target of ezetmibe, a cholesterol absorption inhibitor that is widely used to lower blood cholesterol in humans. Surprisingly, genetic inactivation or ezetimibe inhibition of NPC1L1 in mice was recently found to protect against high fat diet (HFD)-induced obesity (DIO) and associated metabolic disorders. The molecular mechanisms underlying these novel findings remain unknown. The overall goal of the proposed studies is to define how NPC1L1 deficiency affects DIO. In preliminary studies, we found that food intake was identical between wild-type (WT) and NPC1L1 knockout (L1KO) mice, yet L1KO mice were protected against DIO and fatty liver, which was associated with increased expression of genes promoting energy expenditure in brown adipose tissue (BAT) and skeletal muscle. Thus, we hypothesize that NPC1L1 deficiency protects mice from DIO by increasing energy expenditure. We will directly measure energy expenditure, and molecularly define how NPC1L1 deficiency stimulates energy dissipation by measuring metabolic changes at biochemical and gene expression levels in WT and L1KO mice under dietary excess, ezetimibe treatment or fasting conditions. In mice, NPC1L1 is highly expressed in small intestine and only low levels of NPC1L1 mRNA can be detected in non-intestinal tissues. We hypothesize that loss of intestinal NPC1L1 is responsible for resistance to DIO. To directly test this hypothesis, we will cross our newly-created transgenic mice specifically expressing human NPC1L1 in small intestine to L1KO mice, thereby re-establishing intestinal NPC1L1 expression, and determine if this will rescue weight gain in L1KO mice. We will also determine if NPC1L1 deficiency requires a thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) to prevent DIO since we found that D2 expression was substantially elevated in BAT and muscle in L1KO mice, and D2 activation is known to promote energy expenditure. To probe the molecular link between NPC1L1 deficiency and D2 activation, we will examine if bile acid metabolism differs between WT and L1KO mice on HFD because we found that many bile acid sensitive genes were upregulated in the ileum of L1KO mice and bile acids can function as signaling molecules to stimulate energy expenditure via a D2- dependent mechanism. Taken together, these studies will provide important new insight into the role of NPC1L1 in metabolic diseases, and have the potential to reveal new approaches for the prevention and treatment of obesity and associated metabolic risk factors, which contribute substantially to disease morbidity and mortality.

Public Health Relevance

The overall goal of this proposal is to define how genetic inactivation or pharmacologic inhibition of intestinal NPC1L1 influences the development of obesity induced by a high fat diet. Findings from proposed studies hold the promise of revealing new approaches for the prevention and treatment of metabolic diseases such as obesity, type 2 diabetes and nonalcoholic fatty liver diseases. Given that NPC1L1 is the target of ezetimibe, an FDA-approved intestinal cholesterol absorption inhibitor that is widely used to lower blood cholesterol in humans, these studies have enormous translational potential.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Maruvada, Padma
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland College Park
Veterinary Sciences
Schools of Earth Sciences/Natur
College Park
United States
Zip Code
Xie, Ping; Guo, Feng; Ma, Yinyan et al. (2014) Intestinal Cgi-58 deficiency reduces postprandial lipid absorption. PLoS One 9:e91652
Yang, Xiaosong; Wang, Xianfeng; Liu, Dongxu et al. (2014) Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol 28:565-74
Ou, Juanjuan; Miao, Hongming; Ma, Yinyan et al. (2014) Loss of abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition. Cell Rep 9:1798-811
Xie, Ping; Zhu, Hongling; Jia, Lin et al. (2014) Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 237:609-17
Miao, Hongming; Ou, Juanjuan; Ma, Yinyan et al. (2014) Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice. Cell Rep 7:223-35
Ou, Juanjuan; Deng, Jia; Wei, Xing et al. (2013) Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells. Stem Cell Res 11:820-33
Xie, Ping; Jia, Lin; Ma, Yinyan et al. (2013) Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice. Arterioscler Thromb Vasc Biol 33:920-5
Guo, Feng; Ma, Yinyan; Kadegowda, Anil K G et al. (2013) Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice. J Lipid Res 54:2109-20
Miao, Hongming; Zhang, Yang; Lu, Zhongyan et al. (2012) FOXO1 increases CCL20 to promote NF-?B-dependent lymphocyte chemotaxis. Mol Endocrinol 26:423-37
Jia, Lin; Betters, Jenna L; Yu, Liqing (2011) Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol 73:239-59

Showing the most recent 10 out of 15 publications