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• W2019924734 abstract "Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. Careful comparison of dietary compositions in these studies implies a potential role of dietary cholesterol in regulating weight gain. To examine this potential, wild-type (WT) and L1-KO mice were fed one of three sets of diets for various durations: (1) a HFD without added cholesterol for 5 weeks; (2) a high-carbohydrate diet with or without added cholesterol for 5 weeks; or (3) a synthetic HFD with or without added cholesterol for 18 weeks. We found that L1-KO mice were protected against diet-induced weight gain only on a diet without added cholesterol but not on a diet containing 0.16% or 0.2% (w/w) cholesterol, an amount similar to a typical Western diet, regardless of the major energy source of the diet. Food intake and intestinal fat absorption were similar between the two genotypes. Intestinal cholesterol absorption was blocked, and fecal cholesterol excretion increased in L1-KO mice. Under all diets, L1-KO mice were protected from hepatosteatosis. In conclusion, increasing dietary cholesterol restores diet-induced weight gain in mice deficient in NPC1L1-dependent cholesterol absorption. Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. Careful comparison of dietary compositions in these studies implies a potential role of dietary cholesterol in regulating weight gain. To examine this potential, wild-type (WT) and L1-KO mice were fed one of three sets of diets for various durations: (1) a HFD without added cholesterol for 5 weeks; (2) a high-carbohydrate diet with or without added cholesterol for 5 weeks; or (3) a synthetic HFD with or without added cholesterol for 18 weeks. We found that L1-KO mice were protected against diet-induced weight gain only on a diet without added cholesterol but not on a diet containing 0.16% or 0.2% (w/w) cholesterol, an amount similar to a typical Western diet, regardless of the major energy source of the diet. Food intake and intestinal fat absorption were similar between the two genotypes. Intestinal cholesterol absorption was blocked, and fecal cholesterol excretion increased in L1-KO mice. Under all diets, L1-KO mice were protected from hepatosteatosis. In conclusion, increasing dietary cholesterol restores diet-induced weight gain in mice deficient in NPC1L1-dependent cholesterol absorption. Elevated blood total and low-density lipoprotein cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. In addition to de novo biosynthesis and hepatobiliary secretion, intestinal absorption of cholesterol is another major pathway by which the body regulates cholesterol homeostasis in response to fluctuations in cholesterol availability and utilization. Inhibiting this pathway by a cholesterol absorption inhibitor ezetimibe (trade name Zetia) (1Rosenblum S.B. Huynh T. Afonso A. Davis Jr, H.R. Yumibe N. Clader J.W. Burnett D.A. Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.J. Med. Chem. 1998; 41: 973-980Crossref PubMed Scopus (368) Google Scholar) has been shown to significantly reduce plasma total and low-density lipoprotein cholesterol in all mammalian species tested, including humans (2Davis Jr, H.R. Compton D.S. Hoos L. Tetzloff G. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 2032-2038Crossref PubMed Scopus (199) Google Scholar, 3Davis Jr, H.R. Pula K.K. Alton K.B. Burrier R.E. Watkins R.W. The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs.Metabolism. 2001; 50: 1234-1241Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 4van Heek M. Austin T.M. Farley C. Cook J.A. Tetzloff G.G. Davis H.R. Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters.Diabetes. 2001; 50: 1330-1335Crossref PubMed Scopus (82) Google Scholar, 5van Heek M. Compton D.S. Davis H.R. The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys.Eur. J. Pharmacol. 2001; 415: 79-84Crossref PubMed Scopus (132) Google Scholar, 6van Heek M. Farley C. Compton D.S. Hoos L. Davis H.R. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function.Br. J. Pharmacol. 2001; 134: 409-417Crossref PubMed Scopus (191) Google Scholar, 7Gagne C. Bays H.E. Weiss S.R. Mata P. Quinto K. Melino M. Cho M. Musliner T.A. Gumbiner B. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia.Am. J. Cardiol. 2002; 90: 1084-1091Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 8Davidson M.H. McGarry T. Bettis R. Melani L. Lipka L.J. LeBeaut A.P. Suresh R. Sun S. Veltri E.P. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.J. Am. Coll. Cardiol. 2002; 40: 2125-2134Crossref PubMed Scopus (512) Google Scholar, 9Sudhop T. Lutjohann D. Kodal A. Igel M. Tribble D.L. Shah S. Perevozskaya I. von Bergmann K. Inhibition of intestinal cholesterol absorption by ezetimibe in humans.Circulation. 2002; 106: 1943-1948Crossref PubMed Scopus (451) Google Scholar). Each day, large amounts of cholesterol enter the lumen of the small intestine. The daily dietary intake of cholesterol is ∼400 mg in a healthy human consuming a typical Western diet (10Salen G. Ahrens Jr, E.H. Grundy S.M. Metabolism of beta-sitosterol in man.J. Clin. Invest. 1970; 49: 952-967Crossref PubMed Scopus (386) Google Scholar, 11Wang D.Q. Regulation of intestinal cholesterol absorption.Annu. Rev. Physiol. 2007; 69: 221-248Crossref PubMed Scopus (231) Google Scholar). Additionally, ∼800 mg cholesterol is secreted into the gut lumen from bile each day (11Wang D.Q. Regulation of intestinal cholesterol absorption.Annu. Rev. Physiol. 2007; 69: 221-248Crossref PubMed Scopus (231) Google Scholar). The fractional intestinal cholesterol absorption ranges from 29% to 80% in healthy individuals (12Bosner M.S. Lange L.G. Stenson W.F. Ostlund Jr, R.E. Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry.J. Lipid Res. 1999; 40: 302-308Abstract Full Text Full Text PDF PubMed Google Scholar). To be efficiently absorbed, the hydrophobic cholesterol molecule has to cross the unstirred water layer lying between the bulk water phase and the intestinal mucosal cell membrane, which is achieved by its solubilization in mixed micelles containing bile acids, phospholipids, and hydrolytic products of fat (13Turley S.D. Dietschy J.M. Sterol absorption by the small intestine.Curr. Opin. Lipidol. 2003; 14: 233-240Crossref PubMed Scopus (117) Google Scholar). Whether free cholesterol in micelles is taken up passively or actively by absorptive enterocytes had remained elusive until the discovery of ezetimibe (13Turley S.D. Dietschy J.M. Sterol absorption by the small intestine.Curr. Opin. Lipidol. 2003; 14: 233-240Crossref PubMed Scopus (117) Google Scholar). The potency of low doses of ezetimibe in inhibiting intestinal cholesterol absorption strongly supports the notion that intestinal cholesterol absorption is an active and protein-mediated process. The search for this protein resulted in identification of Niemann-Pick C1-Like 1 (NPC1L1) as a cholesterol transporter essential for intestinal cholesterol absorption (14Altmann S.W. Davis Jr, H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1429) Google Scholar). NPC1L1 protein is highly expressed in the small intestine across species and localizes primarily at the apical membrane of absorptive enterocytes (14Altmann S.W. Davis Jr, H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1429) Google Scholar, 15Sane A.T. Sinnett D. Delvin E. Bendayan M. Marcil V. Menard D. Beaulieu J.F. Levy E. Localization and role of NPC1L1 in cholesterol absorption in human intestine.J. Lipid Res. 2006; 47: 2112-2120Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Although humans and nonhuman primates also express NPC1L1 in liver and perhaps other tissues, mouse NPC1L1 protein can only be detected in the small intestine (14Altmann S.W. Davis Jr, H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1429) Google Scholar, 16Davies J.P. Levy B. Ioannou Y.A. Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1.Genomics. 2000; 65: 137-145Crossref PubMed Scopus (188) Google Scholar, 17Yu L. Bharadwaj S. Brown J.M. Ma Y. Du W. Davis M.A. Michaely P. Liu P. Willingham M.C. Rudel L.L. Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake.J. Biol. Chem. 2006; 281: 6616-6624Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 18Temel 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.J. Clin. Invest. 2007; 117: 1968-1978Crossref PubMed Scopus (305) Google Scholar). NPC1L1 knockout (L1-KO) mice do not absorb cholesterol from the intestinal lumen and thus have a corresponding increase in fecal cholesterol excretion and compensatory upregulation of de novo cholesterol biosynthesis, similar to phenotypes observed in ezetimibe-treated animals (14Altmann S.W. Davis Jr, H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1429) Google Scholar, 19Davis Jr, H.R. Zhu L.J. Hoos L.M. Tetzloff G. Maguire M. Liu J. Yao X. Iyer S.P. Lam M.H. Lund E.G. et al.Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis.J. Biol. Chem. 2004; 279: 33586-33592Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar). Because inhibiting intestinal cholesterol absorption increases endogenous cholesterol synthesis, ezetimibe is often prescribed together with a statin that inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting enzyme of cholesterol synthesis (20Tobert J.A. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.Nat. Rev. Drug Discov. 2003; 2: 517-526Crossref PubMed Scopus (643) Google Scholar, 21Endo A. The discovery and development of HMG-CoA reductase inhibitors.J. Lipid Res. 1992; 33: 1569-1582Abstract Full Text PDF PubMed Google Scholar). Subsequent genetic, animal, and cell biology studies support the notion that NPC1L1 is the molecular target of ezetimibe (14Altmann S.W. Davis Jr, H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1429) Google Scholar, 17Yu L. Bharadwaj S. Brown J.M. Ma Y. Du W. Davis M.A. Michaely P. Liu P. Willingham M.C. Rudel L.L. Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake.J. Biol. Chem. 2006; 281: 6616-6624Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 22Cohen J.C. Pertsemlidis A. Fahmi S. Esmail S. Vega G.L. Grundy S.M. Hobbs H.H. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.Proc. Natl. Acad. Sci. USA. 2006; 103: 1810-1815Crossref PubMed Scopus (328) Google Scholar, 23Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar, 24Wang J. Williams C. Hegele R. Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177Crossref PubMed Scopus (67) Google Scholar, 25Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 26Garcia-Calvo M. Lisnock J. Bull H.G. Hawes B.E. Burnett D.A. Braun M.P. Crona J.H. Davis Jr, H.R. Dean D.C. Detmers P.A. et al.The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).Proc. Natl. Acad. Sci. USA. 2005; 102: 8132-8137Crossref PubMed Scopus (650) Google Scholar, 27Weinglass A.B. Kohler M. Schulte U. Liu J. Nketiah E.O. Thomas A. Schmalhofer W. Williams B. Bildl W. McMasters D.R. et al.Extracellular loop C of NPC1L1 is important for binding to ezetimibe.Proc. Natl. Acad. Sci. USA. 2008; 105: 11140-11145Crossref PubMed Scopus (91) Google Scholar). Interestingly, ezetimibe treatment or genetic inactivation of NPC1L1 was recently shown to improve many aspects of metabolic syndrome, including insulin resistance and hepatic steatosis (28Davies J.P. Scott C. Oishi K. Liapis A. Ioannou Y.A. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia.J. Biol. Chem. 2005; 280: 12710-12720Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 29Assy N. Grozovski M. Bersudsky I. Szvalb S. Hussein O. Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease.World J. Gastroenterol. 2006; 12: 4369-4376Crossref PubMed Scopus (49) Google Scholar, 30Deushi M. Nomura M. Kawakami A. Haraguchi M. Ito M. Okazaki M. Ishii H. Yoshida M. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome.FEBS Lett. 2007; 581: 5664-5670Crossref PubMed Scopus (147) Google Scholar, 31Nozaki Y. Fujita K. Yoneda M. Wada K. Shinohara Y. Takahashi H. Kirikoshi H. Inamori M. Kubota K. Saito S. et al.Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.J. Hepatol. 2009; 51: 548-556Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 32Zheng S. Hoos L. Cook J. Tetzloff G. Davis Jr, H. van Heek M. Hwa J.J. Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice.Eur. J. Pharmacol. 2008; 584: 118-124Crossref PubMed Scopus (142) Google Scholar, 33Labonte E.D. Camarota L.M. Rojas J.C. Jandacek R.J. Gilham D.E. Davies J.P. Ioannou Y.A. Tso P. Hui D.Y. Howles P.N. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G776-G783Crossref PubMed Scopus (97) Google Scholar, 34Yagi S. Akaike M. Aihara K. Iwase T. Ishikawa K. Yoshida S. Sumitomo-Ueda Y. Kusunose K. Niki T. Yamaguchi K. et al.Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia.J. Atheroscler. Thromb. 2010; 17: 173-180Crossref PubMed Scopus (40) Google Scholar). For example, L1-KO mice on a pure C57BL/6 background or ezetimibe-treated wild-type (WT) C57BL/6 mice are resistant to weight gain on a high-fat diet (HFD) containing trace amounts of cholesterol (31Nozaki Y. Fujita K. Yoneda M. Wada K. Shinohara Y. Takahashi H. Kirikoshi H. Inamori M. Kubota K. Saito S. et al.Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.J. Hepatol. 2009; 51: 548-556Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 33Labonte E.D. Camarota L.M. Rojas J.C. Jandacek R.J. Gilham D.E. Davies J.P. Ioannou Y.A. Tso P. Hui D.Y. Howles P.N. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G776-G783Crossref PubMed Scopus (97) Google Scholar). L1-KO mice on 129/OlaHsd background, however, gain similar weight as WT controls after 24 weeks on a diet containing 40% calories from butter fat and 0.15% cholesterol (35Davis Jr, H.R. Hoos L.M. Tetzloff G. Maguire M. Zhu L.J. Graziano M.P. Altmann S.W. Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE−/− mice.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 841-849Crossref PubMed Scopus (112) Google Scholar). In another study examining the protective role of ezetimibe against the development of fatty liver disease, ezetimibe treatment for 4 weeks did not prevent weight gain in C57BL/6 mice fed a HFD containing 0.12% cholesterol (32Zheng S. Hoos L. Cook J. Tetzloff G. Davis Jr, H. van Heek M. Hwa J.J. Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice.Eur. J. Pharmacol. 2008; 584: 118-124Crossref PubMed Scopus (142) Google Scholar). While these discrepancies among different studies may be attributable to differences in genetic background, gene-targeting strategies, experimental duration, and/or dietary fat composition, we noticed that resistance to diet-induced weight gain was found only in L1-KO mice or ezetimibe-treated mice fed a low (<0.02%, w/w) cholesterol-containing diet (31Nozaki Y. Fujita K. Yoneda M. Wada K. Shinohara Y. Takahashi H. Kirikoshi H. Inamori M. Kubota K. Saito S. et al.Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.J. Hepatol. 2009; 51: 548-556Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 33Labonte E.D. Camarota L.M. Rojas J.C. Jandacek R.J. Gilham D.E. Davies J.P. Ioannou Y.A. Tso P. Hui D.Y. Howles P.N. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice.Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295: G776-G783Crossref PubMed Scopus (97) Google Scholar) but not in those fed a high (0.15% or 0.12%, w/w) cholesterol diet (32Zheng S. Hoos L. Cook J. Tetzloff G. Davis Jr, H. van Heek M. Hwa J.J. Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice.Eur. J. Pharmacol. 2008; 584: 118-124Crossref PubMed Scopus (142) Google Scholar, 35Davis Jr, H.R. Hoos L.M. Tetzloff G. Maguire M. Zhu L.J. Graziano M.P. Altmann S.W. Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE−/− mice.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 841-849Crossref PubMed Scopus (112) Google Scholar). This led us to hypothesize that dietary cholesterol modulates weight gain in NPC1L1-deficient mice. To systemically determine if NPC1L1 deficiency prevents weight gain in a dietary cholesterol-dependent manner, we fed L1-KO mice and WT controls a diet containing either a low (<0.02%, w/w) or a high (∼0.2%, w/w) amount of cholesterol for 5 weeks or 18 weeks, and monitored body weight changes and other metabolic parameters in these animals. Our findings clearly demonstrate that dietary supplementation of cholesterol rescues weight gain in L1-KO mice on both HFD and high-carbohydrate diet (HCD). Future studies are needed to solve the conundrum of how increasing dietary cholesterol restores the diet-induced weight gain in mice deficient in intestinal cholesterol absorption. L1-KO mice were created using C57BL/6 embryonic stem cells, thus having a pure C57BL/6 background (28Davies J.P. Scott C. Oishi K. Liapis A. Ioannou Y.A. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia.J. Biol. Chem. 2005; 280: 12710-12720Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). These mice have been crossed to WT C57BL/6 mice for at least four generations before the use for this study. L1-KO mice and their controls were maintained on the pure C57BL/6 background for all the experiments. All mice were housed in a specific pathogen-free animal facility in plastic cages at 22°C, with a daylight cycle from 6 AM to 6 PM. The mice were provided with water and standard chow diet (Prolab RMH 3000; LabDiet, Brentwood, MO) ad libitum, unless stated otherwise. All animal procedures were approved by the Institutional Animal Care and Use Committee at Wake Forest University Health Sciences. For the first short-term study, male L1-KO and WT C57BL/6 mice were fed a HFD containing a trace amount of cholesterol (∼0.007%, w/w) (HFD1-C) (TD.93075; Harlan Teklad, Madison, WI) for 5 weeks, starting at 8 weeks of age. This diet contains 54.8% calories from fat, 21.2% calories from protein, and 24% calories from carbohydrates. The fatty acid composition of total fat in this diet is included in supplementary Table I. For the second short-term experiment, 8-week-old male L1-KO mice and WT controls were fed a synthetic high-carbohydrate diet (HCD) containing either <0.02% cholesterol (HCD-C) or ∼0.2% cholesterol (HCD+C) for 5 weeks. These synthetic diets were made at the Diet Core of Wake Forest University School of Medicine, which has more than 40 years of experience in preparing animal diets. Ingredients of these diets are presented in supplementary Table II. Both carbohydrate diets have identical ingredients except cholesterol, containing 11% calories from palm oil, 72% calories from carbohydrates, and 17% calories from protein. The fatty acid composition of the fat in this diet is included in supplementary Table I. The third study was a long-term HFD study. Six-week-old male L1-KO mice and their WT controls were fed a synthetic HFD containing either a low (<0.02%, w/w, HFD-C) or a high (∼0.16%, w/w, HFD+C) amount of cholesterol for 18 weeks. These synthetic diets were made at the Diet Core of Wake Forest University School of Medicine. Ingredients of these diets are presented in supplementary Table II. The fatty acid composition of these diets is included in supplementary Table I. During the diet feeding period, body weight was monitored weekly. Food intake was monitored daily for 2 weeks after 16 weeks of diet feeding. Plasma insulin was measured by Ultra Sensitive Mouse Insulin Elisa Kit (Crystal Chem, Inc., Downers Grove, IL). Blood glucose was measured directly by Glucometer (Bayer Contour, Tarrytown, NY) via a tail nick. Plasma total cholesterol, free cholesterol, and triglyceride concentrations were analyzed by enzymatic assay as previously described (36Tang W. Ma Y. Jia L. Ioannou Y.A. Davies J.P. 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; 28: 448-454Crossref PubMed Scopus (43) Google Scholar). The amount of cholesteryl ester was calculated by subtracting free cholesterol from total cholesterol and multiplying by 1.67 to convert to cholesteryl ester mass. Plasma concentrations of nonesterified fatty acids were measured by colorimetric assay [HR Series NEFA-HR (2Davis Jr, H.R. Compton D.S. Hoos L. Tetzloff G. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 2032-2038Crossref PubMed Scopus (199) Google Scholar); Wako, Richmond, VA] following the manufacturer's instructions. At the end of diet studies, mice were euthanized after a 4 h fast. Livers were removed, weighed, and snap-frozen in liquid nitrogen for liver lipid analyses as we have described previously (18Temel 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.J. Clin. Invest. 2007; 117: 1968-1978Crossref PubMed Scopus (305) Google Scholar). In week 18 of the long-term diet experiment, mice were individually housed for the determination of fractional cholesterol absorption and fecal neutral sterol excretion as described previously (37Tang W. Ma Y. Jia L. Ioannou Y.A. Davies J.P. Yu L. Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8.J. Lipid Res. 2009; 50: 293-300Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Mass of dietary cholesterol absorption into the body was calculated by multiplying food intake, dietary cholesterol content, and percentage of cholesterol absorption (38Repa J.J. Buhman K.K. Farese Jr, R.V. Dietschy J.M. Turley S.D. ACAT2 deficiency limits cholesterol absorption in the cholesterol-fed mouse: impact on hepatic cholesterol homeostasis.Hepatology. 2004; 40: 1088-1097Crossref PubMed Scopus (96) Google Scholar). Total RNAs were extracted from jejuna using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. The qPCR was performed as described previously (39Yang J. Goldstein J.L. Hammer R.E. Moon Y.A. Brown M.S. Horton J.D. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene.Proc. Natl. Acad. Sci. USA. 2001; 98: 13607-13612Crossref PubMed Scopus (190) Google Scholar). All primers used for qPCR have been published previously (39Yang J. Goldstein J.L. Hammer R.E. Moon Y.A. Brown M.S. Horton J.D. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene.Proc. Natl. Acad. Sci. USA. 2001; 98: 13607-13612Crossref PubMed Scopus (190) Google Scholar, 40Tang W. Ma Y. Yu L. Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice.Hepatology. 2006; 44: 1259-1266Crossref PubMed Scopus (22) Google Scholar). After 16 weeks of diet feeding, mice were individually housed and fed a test diet for three days, which contained the same calories and fatty acid composition as the previous diet, except that 5% of fat was replaced by sucrose poly-behenate as a nonabsorbable marker. Fecal samples were collected for three days, and the fatty acid composition was measured in both fecal and diet samples by gas chromatography. Fractional absorption of total and individual fatty acids was calculated as previously described (41Jandacek R.J. Heubi J.E. Tso P. A novel, noninvasive method for the measurement of intestinal fat absorption.Gastroenterology. 2004; 127: 139-144Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). For glucose tolerance test, mice were fasted for 10 h. After measuring the baseline blood glucose concentration from a tail cut by a Glucometer test strip (Bayer Ascensia Contour, Tarrytown, NY), mice were injected intraperitoneally with 20% glucose at 1.5 mg/g body weight. Blood glucose concentrations were then measured at 15, 30, 60, and 120 min after glucose injection. For insulin tolerance test, mice were fasted for 6 h. After measuring the baseline blood glucose concentration, mice were injected intraperitoneally with recombinant human insulin (Novo Nordisk, Inc., Princeton, NY) at 1.2 mU/g body weight. Blood glucose concentrations were then measured at 15, 30, 60, and 120 min after insulin administration. All data are presented as mean ± SEM. The differences between the mean values of L1-KO mice and WT mice on the same diet, or between diet groups of mice of the same genotype, were tested for statistical significance by the two-tailed Student's t-test. Statistical significance was accepted at a value of P < 0.05. To determine the effect of HFD containing no added cholesterol on weight gain in L1-KO mice, mice were fed the HFD1-C as described in “Materials and Methods.” L1-KO and WT mice had similar weight at birth and at the time when the diet was started (Fig. 1A). Interestingly, L1-KO mice began to gain significantly less weight compared with WT mice after one week on this diet (Fig. 1B). After five weeks of diet feeding, L1-KO mice gained only ∼2 g of weight, whereas WT mice gained nearly 5 g of body weight (Table 1).TABLE 1.Plasma and hepatic parameters of WT and L1-KO mice fed HFD1-C diet for five weeksLow Cholesterol, High-Fat DietParameterWT MiceL1-KO MiceBW (g)26.8 ± 0.823.8 ± 0.2aP < 0.05.WAT weight (g)0.99 ± 0.040.34 ± 0.03bP < 0.001.WAT to BW ratio (%)3.74 ± 0.141.43 ± 0.13bP < 0.001.Liver weight (g)1.1 ± 0.050.9 ± 0.03aP < 0.05.Liver to BW ratio (%)4.2 ± 0.133.8 ± 0.12aP < 0.05.Plasma TC (mg/dl)129.8 ± 9.8115.1 ± 8.1Plasma FC (mg/dl)33.9 ± 2.828.7 ± 1.5Plasma CE (mg/dl)160.1 ± 12.4144.3 ± 11.8Plasma TG (mg/dl)49.1 ± 8.331.3 ± 3.1Plasma NEFA (mmol/l)0.37 ± 0.030.24 ± 0.05Hepatic TC (mg/g WW)2.1 ± 0.312.0 ± 0.08Hepatic TG (mg/g WW)24.9 ± 6.595.2 ± 0.79aP < 0.05.Mice were fasted for 4 h prior to plasma and liver lipids analysis; n = 4–7 for liver lipids and n = 6–7 for other measurements. BW, body weight; CE, cholesteryl ester; FC, free cholesterol; HFD1-C, low-cholesterol, high-fat diet; L1-KO, NPC1L1 knockout; NEFA, nonesterified fatty acid; TC, total cholesterol; TG, triglyceride; WAT, white adipose tissue; WW, wet weight; WT, wild-type.a P < 0.05.b P < 0.001." @default.
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• W2019924734 date "2010-10-01" @default.
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• W2019924734 title "Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1" @default.
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• W2019924734 doi "https://doi.org/10.1194/jlr.m008599" @default.
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