Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet

Dick C Chan, Gerald F Watts, Seng Khee Gan, Esther M M Ooi, P Hugh R Barrett, Dick C Chan, Gerald F Watts, Seng Khee Gan, Esther M M Ooi, P Hugh R Barrett

Abstract

Objective: Nonalcoholic fatty liver disease is highly prevalent in obese and type 2 diabetic individuals and is strongly associated with dyslipidemia and inflammation. Weight loss and/or pharmacotherapy are commonly used to correct these abnormalities.

Research design and methods: We performed a 16-week intervention trial of a hypocaloric, low-fat diet plus 10 mg/day ezetimibe (n = 15) versus a hypocaloric, low-fat diet alone (n = 10) on intrahepatic triglyceride (IHTG) content, plasma high sensitivity-C-reactive protein (hs-CRP), adipocytokines, and fetuin-A concentrations and apolipoprotein (apo)B-100 kinetics in obese subjects. ApoB-100 metabolism was assessed using stable isotope tracer kinetics and compartmental modeling; liver and abdominal fat contents were determined by magnetic resonance techniques.

Results: Both weight loss and ezetimibe plus weight loss significantly (all P < 0.05) reduced body weight, visceral and subcutaneous adipose tissues, insulin resistance and plasma triglycerides, VLDL-apoB-100, apoC-III, fetuin-A, and retinol-binding protein-4 and increased plasma adiponectin concentrations. Compared with weight loss alone, ezetimibe plus weight loss significantly (all P < 0.05) decreased IHTG content (-18%), plasma hs-CRP (-53%), interleukin-6 (-24%), LDL cholesterol (-18%), campesterol (-59%), and apoB-100 (-14%) levels, with a significant increase in plasma lathosterol concentrations (+43%). The LDL-apoB-100 concentration also significantly fell with ezetimibe plus weight loss (-12%), chiefly owing to an increase in the corresponding fractional catabolic rate (+29%). The VLDL-apoB-100 secretion rate fell with both interventions, with no significant independent effect of ezetimibe.

Conclusions: Addition of ezetimibe to a moderate weight loss diet in obese subjects can significantly improve hepatic steatosis, inflammation, and LDL-apoB-100 metabolism.

Figures

Figure 1
Figure 1
Effects of weight loss and ezetimibe plus weight loss on intrahepatic triglyceride content in obese subjects. There was no significant group difference in preintervention intrahepatic triglyceride content (P > 0.05). *P < 0.05, value significantly different from baseline value. **Value significantly different using general linear modeling after adjustment for weight loss group.

References

    1. Torres DM, Harrison SA: Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008; 134: 1682– 1698
    1. Kotronen A, Yki-Järvinen H: Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28: 27– 38
    1. Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697– 738
    1. Ginsberg HN, Huang LS: The insulin resistance syndrome: impact on lipoprotein metabolism and atherothrombosis. J Cardiovasc Risk 2000; 7: 325– 331
    1. Utzschneider KM, Kahn SE: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006; 91: 4753– 4761
    1. Mazzone T, Foster D, Chait A: In vivo stimulation of low-density lipoprotein degradation by insulin. Diabetes 1984; 33: 333– 338
    1. Van Gaal LF, Wauters MA, De Leeuw IH: The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord 1997; 21: S5– S9
    1. Riches FM, Watts GF, Hua J, Stewart GR, Naoumova RP, Barrett PH: Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab 1999; 84: 2854– 2861
    1. Jeu L, Cheng JW: Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor. Clin Ther 2003; 25: 2352– 2387
    1. 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; 117: 1968– 1978
    1. Tremblay AJ, Lamarche B, Cohn JS, Hogue JC, Couture P: Effect of ezetimibe on the in vivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol 2006; 26: 1101– 1106
    1. Tremblay AJ, Lamarche B, Hogue JC, Couture P: Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J Lipid Res 2009; 50: 1463– 1471
    1. Deushi 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– 5670
    1. Watts GF, Barrett PH, Ji J, Serone AP, Chan DC, Croft KD, Loehrer F, Johnson AG: Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes 2003; 52: 803– 811
    1. Beghin L, Duhal N, Poulain P, Hauw P, Lacroix B, Lecerf JM, Bonte JP, Fruchart JC, Luc G: Measurement of apolipoprotein B concentration in plasma lipoproteins by combining selective precipitation and mass spectrometry. J Lipid Res 2000; 41: 1172– 1176
    1. Rasouli N, Kern PA: Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 2008; 93: s64– s73
    1. Ix JH, Shlipak MG, Brandenburg VM, Ali S, Ketteler M, Whooley MA: Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study. Circulation 2006; 113: 1760– 1767
    1. Telford DE, Sutherland BG, Edwards JY, Andrews JD, Barrett PH, Huff MW: The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res 2007; 48: 699– 708
    1. Horton JD, Goldstein JL, Brown MS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125– 1131
    1. Schroepfer GJ, Jr: Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 2000; 80: 361– 554
    1. Staprans I, Pan XM, Rapp JH, Moser AH, Feingold KR: Ezetimibe inhibits the incorporation of dietary oxidized cholesterol into lipoproteins. J Lipid Res 2006; 47: 2575– 2580
    1. Sager PT, Capece R, Lipka L, Strony J, Yang B, Suresh R, Mitchel Y, Veltri E: Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients. Atherosclerosis 2005; 179: 361– 367
    1. Pearson TA, Ballantyne CM, Veltri E, Shah A, Bird S, Lin J, Rosenberg E, Tershakovec AM: Pooled analyses of effects on C-reactive protein and low density lipoprotein cholesterol in placebo-controlled trials of ezetimibe monotherapy or ezetimibe added to baseline statin therapy. Am J Cardiol 2009; 103: 369– 374
    1. Weinhold B, Rüther U: Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 1997; 327: 425– 429
    1. Tannock LR, O'Brien KD, Knopp RH, Retzlaff B, Fish B, Wener MH, Kahn SE, Chait A: Cholesterol feeding increases C-reactive protein and serum amyloid A levels in lean insulin-sensitive subjects. Circulation 2005; 111: 3058– 3062

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel