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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK085176-01
Application #
7768744
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Maruvada, Padma
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Ou, Juanjuan; Miao, Hongming; Ma, Yinyan et al. (2018) Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition. Cell Rep 24:2795-2797
Shin, Hyunsu; Ma, Yinyan; Chanturiya, Tatyana et al. (2017) Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice. Cell Metab 26:764-777.e5
Meng, Xiangyu; Guo, Jun; Fang, Weiwei et al. (2016) Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5'-Monophosphate (AMP)-activated Protein Kinase ?1. J Biol Chem 291:10625-34
Li, Fenfen; Wu, Rui; Cui, Xin et al. (2016) Histone Deacetylase 1 (HDAC1) Negatively Regulates Thermogenic Program in Brown Adipocytes via Coordinated Regulation of Histone H3 Lysine 27 (H3K27) Deacetylation and Methylation. J Biol Chem 291:4523-36
Cao, Qiang; Cui, Xin; Wu, Rui et al. (2016) Myeloid Deletion of ?1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice. Diabetes 65:1565-76
Wang, Xianfeng; Cao, Qiang; Yu, Liqing et al. (2016) Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight 1:e87748
Xie, Ping; Kadegowda, Anil K G; Ma, Yinyan et al. (2015) Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice. Endocrinology 156:1648-58
Miao, Hongming; Ou, Juanjuan; Zhang, Xuan et al. (2015) Macrophage CGI-58 deficiency promotes IL-1? transcription by activating the SOCS3-FOXO1 pathway. Clin Sci (Lond) 128:493-506
Gan, Lixia; Xiang, Wei; Xie, Bin et al. (2015) Molecular mechanisms of fatty liver in obesity. Front Med 9:275-87
Zhong, Chun-Yan; Sun, Wei-Wei; Ma, Yinyan et al. (2015) Microbiota prevents cholesterol loss from the body by regulating host gene expression in mice. Sci Rep 5:10512

Showing the most recent 10 out of 26 publications