Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide.

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action. METHODS Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined. RESULTS ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice. CONCLUSIONS This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.

[1]  A. Kimmel,et al.  Functional Compensation for Adipose Differentiation-related Protein (ADFP) by Tip47 in an ADFP Null Embryonic Cell Line* , 2006, Journal of Biological Chemistry.

[2]  M. Lazar,et al.  Loss of Resistin Improves Glucose Homeostasis in Leptin Deficiency , 2006, Diabetes.

[3]  D. Brasaemle,et al.  A proposed model of fat packaging by exchangeable lipid droplet proteins , 2006, FEBS letters.

[4]  J. Borén,et al.  Adipocyte Differentiation-Related Protein Promotes Fatty Acid Storage in Cytosolic Triglycerides and Inhibits Secretion of Very Low–Density Lipoproteins , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[5]  B. Monia,et al.  Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. , 2006, The Journal of clinical investigation.

[6]  S. Ulven,et al.  adipose differentiation-related protein in liver , 2022 .

[7]  G. Shulman,et al.  Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. , 2006, The Journal of clinical investigation.

[8]  T. Okumura,et al.  Up-regulation of ADRP in fatty liver in human and liver steatosis in mice fed with high fat diet. , 2006, Biochemical and biophysical research communications.

[9]  B. Chang,et al.  Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein , 2006, Molecular and Cellular Biology.

[10]  H. Arai,et al.  ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells Published, JLR Papers in Press, October 17, 2005. , 2006, Journal of Lipid Research.

[11]  D. Rader,et al.  Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339 Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.D500019-JLR200 , 2005, Journal of Lipid Research.

[12]  B. Monia,et al.  Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice , 2005, Hepatology.

[13]  B. Schreiber,et al.  PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes , 2005 .

[14]  N. Wolins,et al.  S3-12, Adipophilin, and TIP47 Package Lipid in Adipocytes* , 2005, Journal of Biological Chemistry.

[15]  A. Dobrzyń,et al.  Stearoyl‐CoA desaturase as a new drug target for obesity treatment , 2005, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[16]  M. Graham,et al.  An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M400492-JLR200 , 2005, Journal of Lipid Research.

[17]  Margaret S. Wu,et al.  Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. , 2005, The Journal of clinical investigation.

[18]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[19]  P. Angulo,et al.  Nonalcoholic fatty liver disease. , 2002, Revista de gastroenterologia de Mexico.

[20]  A. Kimmel,et al.  Role of PAT proteins in lipid metabolism. , 2005, Biochimie.

[21]  R. Ahima,et al.  A novel aminosterol reverses diabetes and fatty liver disease in obese mice. , 2004, Journal of hepatology.

[22]  P. Saha,et al.  Metabolic Adaptations in the Absence of Perilipin , 2004, Journal of Biological Chemistry.

[23]  R. Ahima,et al.  Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. , 2004, Diabetes.

[24]  R. Ahima,et al.  Adiponectin acts in the brain to decrease body weight , 2004, Nature Medicine.

[25]  M. Jaye,et al.  Adipophilin Enhances Lipid Accumulation and Prevents Lipid Efflux From THP-1 Macrophages: Potential Role in Atherogenesis , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[26]  M. Lazar,et al.  Regulation of Fasted Blood Glucose by Resistin , 2004, Science.

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

[28]  F. Brancati,et al.  The prevalence and etiology of elevated aminotransferase levels in the United States , 2003, American Journal of Gastroenterology.

[29]  R. Ahima,et al.  Divergent effects of leptin in mice susceptible or resistant to obesity. , 2002, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[30]  H. Nawata,et al.  ADRP stimulates lipid accumulation and lipid droplet formation in murine fibroblasts. , 2002, American journal of physiology. Endocrinology and metabolism.

[31]  C. Deng,et al.  Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Gorenstein,et al.  Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice , 2000, Nature Genetics.

[33]  G. Serrero,et al.  Adipose Differentiation Related Protein (ADRP) Expressed in Transfected COS-7 Cells Selectively Stimulates Long Chain Fatty Acid Uptake* , 1999, The Journal of Biological Chemistry.

[34]  H. Rackwitz,et al.  Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases , 1998, Cell and Tissue Research.

[35]  T. Barber,et al.  Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein. , 1997, Journal of lipid research.

[36]  N. Anderson,et al.  Induction of the adipose differentiation-related protein in liver of etomoxir-treated rats. , 1996, Biochemical and biophysical research communications.

[37]  G. Serrero,et al.  Isolation and characterization of a full-length cDNA coding for an adipose differentiation-related protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.