Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.

BACKGROUND & AIMS Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is due to an imbalance between intrahepatic triglyceride (IHTG) production and export. The purpose of this study was to evaluate TG metabolism in adipose tissue and liver in NAFLD. METHODS Fatty acid, VLDL-TG, and VLDL-apolipoprotein B-100 (apoB100) kinetics were assessed by using stable isotope tracers in 14 nondiabetic obese subjects with NAFLD (IHTG, 22.7% +/- 2.0%) and 14 nondiabetic obese subjects with normal IHTG content (IHTG, 3.4% +/- 0.4%), matched on age, sex, body mass index, and percent body fat. RESULTS Compared with the normal IHTG group, the NAFLD group had greater rates of palmitate release from adipose tissue into plasma (85.4 +/- 6.6 and 114.1 +/- 8.1 micromol/min, respectively; P = .01) and VLDL-TG secretion (11.4 +/- 1.1 and 24.3 +/- 3.1 micromol/min, respectively; P = .001); VLDL-apoB100 secretion rates were not different between groups. The increase in VLDL-TG secretion was primarily due to an increased contribution from "nonsystemic" fatty acids, presumably derived from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis. VLDL-TG secretion rate increased linearly with increasing IHTG content in subjects with normal IHTG but reached a plateau when IHTG content was >/=10% (r = 0.618, P < .001). CONCLUSIONS Obese persons with NAFLD have marked alterations in both adipose tissue (increased lipolytic rates) and hepatic (increased VLDL-TG secretion) TG metabolism. Fatty acids derived from nonsystemic sources are responsible for the increase in VLDL-TG secretion. However, the increase in hepatic TG export is not adequate to normalize IHTG content.

[1]  J. Stockman.  Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia , 2008 .

[2]  Amalia Gastaldelli,et al.  Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. , 2007, Gastroenterology.

[3]  B. S. Mohammed,et al.  Women produce fewer but triglyceride-richer very low-density lipoproteins than men. , 2007, The Journal of clinical endocrinology and metabolism.

[4]  B. Neuschwander‐Tetri.  Fatty liver and the metabolic syndrome , 2007, Current opinion in gastroenterology.

[5]  S. Klein,et al.  Assessment of intrahepatic triglyceride content using magnetic resonance spectroscopy. , 2007, Journal of the cardiometabolic syndrome.

[6]  J. Barkin.  Gastric Bypass Surgery Improves Metabolic and Hepatic Abnormalities Associated With Nonalcoholic Fatty Liver Disease , 2007 .

[7]  T. Shirasawa,et al.  CuZn-SOD Deficiency Causes ApoB Degradation and Induces Hepatic Lipid Accumulation by Impaired Lipoprotein Secretion in Mice* , 2006, Journal of Biological Chemistry.

[8]  I. Goldberg,et al.  Ins and outs modulating hepatic triglyceride and development of nonalcoholic fatty liver disease. , 2006, Gastroenterology.

[9]  B. S. Mohammed,et al.  Lipid metabolism response to a single, prolonged bout of endurance exercise in healthy young men. , 2006, American journal of physiology. Endocrinology and metabolism.

[10]  A. Häkkinen,et al.  Overproduction of large VLDL particles is driven by increased liver fat content in man , 2006, Diabetologia.

[11]  Bernt Wennberg,et al.  Overproduction of VLDL1 Driven by Hyperglycemia Is a Dominant Feature of Diabetic Dyslipidemia , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[12]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[13]  K. Lindor,et al.  Nonalcoholic fatty liver disease , 2005, Canadian Medical Association Journal.

[14]  E. Ferrannini,et al.  Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms , 2005, Diabetologia.

[15]  S. Grundy,et al.  Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. , 2005, American journal of physiology. Endocrinology and metabolism.

[16]  J. Levy,et al.  Use and abuse of HOMA modeling. , 2004, Diabetes care.

[17]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[18]  M. Beylot,et al.  Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. , 2003, Diabetes & metabolism.

[19]  S. Klein,et al.  What does the measurement of whole-body fatty acid rate of appearance in plasma by using a fatty acid tracer really mean? , 2003, Diabetes.

[20]  S. Klein,et al.  Effect of sex and obesity on basal VLDL-triacylglycerol kinetics. , 2003, The American journal of clinical nutrition.

[21]  S. Klein,et al.  Effect of weight loss on VLDL-triglyceride and apoB-100 kinetics in women with abdominal obesity. , 2003, American journal of physiology. Endocrinology and metabolism.

[22]  A. Sanyal,et al.  AGA technical review on nonalcoholic fatty liver disease. , 2002, Gastroenterology.

[23]  A. Häkkinen,et al.  Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. , 2002, The Journal of clinical endocrinology and metabolism.

[24]  K. Nair,et al.  Apolipoprotein synthesis in nonalcoholic steatohepatitis , 2002, Hepatology.

[25]  S. Klein,et al.  Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover. , 2002, Journal of lipid research.

[26]  Claude Pichard,et al.  Dual-energy X-ray absorptiometry and body composition: differences between devices and comparison with reference methods. , 2002, Nutrition.

[27]  J. Clore,et al.  Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. , 2001, Gastroenterology.

[28]  D. Hachey,et al.  Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment. , 1999, Journal of lipid research.

[29]  G. Lewis,et al.  Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. , 1995, The Journal of clinical investigation.

[30]  R M Peshock,et al.  Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers. , 1994, Journal of lipid research.

[31]  L. Mandarino,et al.  Interaction between glucose and free fatty acid metabolism in human skeletal muscle. , 1993, The Journal of clinical investigation.

[32]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.

[33]  R. DeFronzo,et al.  Effect of fatty acids on glucose production and utilization in man. , 1983, The Journal of clinical investigation.

[34]  A. Kissebah,et al.  Integrated Regulation of Very Low Density Lipoprotein Triglyceride and Apolipoprotein-B Kinetics in Non-insulin-dependent Diabetes Mellitus , 1982, Diabetes.

[35]  D. Steinberg,et al.  Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins. , 1980, The American journal of physiology.

[36]  L. Carlson,et al.  Quantitative and qualitative serum lipoprotein analysis. Part 1. Studies in healthy men and women. , 1975, Atherosclerosis.

[37]  R. Steele,et al.  INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT * , 1959, Annals of the New York Academy of Sciences.