CORRESPONDENCE

Peroxisome Proliferator–Activated Receptor-� Induces Insulin-Induced Gene-1 and SuppressesHepatic Lipogenesis in Obese Diabetic Mice

To the Editor:

We read with interest the article by Qin et al.1 and the editorialcomments by Andrews et al.2 regarding an elegantly revealed novelmechanism by which peroxisome proliferator-activated receptor-�(PPAR�) regulates lipogenesis and suggesting its potential therapeuticuse in liver steatosis or more appropriately non-alcoholic fatty liverdisease. The authors strongly demonstrated that treatment withGW0742, the PPAR� agonist, or PPAR� overexpression markedlyreduced intracellular lipid accumulation in the hepatocytes. Themechanism offered by them is that PPAR� acts by suppressing sterolregulatory element-binding protein-1 (SREBP-1) activity and by in-ducing the expression of insulin-induced gene-1 (Insig-1).1 The up-regulation of Insig-1 reduces lipid synthesis by preventing SREBPsfrom entering the Golgi apparatus for proteolytic generation of theirtranscriptionally active forms, thereby limiting the induction ofSREBP target genes and hence lipid synthesis.

The role of PPAR� agonists in reducing body fat has been studiedby various investigators. In a study by Choi et al.,3 it was shown that inthe visceral adipose tissue of PPAR� agonist (L-165041)–treated rats,visfatin and adiponectin messenger RNA levels are significantly in-creased, suggesting that the PPAR� agonist has regulatory effects on avariety of adipokines. Similarly, another PPAR� agonist, GW501516,has been envisioned as a useful strategy against human metabolic syn-drome and related diseases.4

Although in this study the authors have shown interesting obser-vations, as clinicians, in our opinion, data from basic research studiesneeds to be transformed into clinical practice with caution. First, thecause–effect relationship of fatty liver and insulin resistance has been amatter of debate.5 Second, the metabolic syndrome is the outcome ofa complex interaction between numerous hereditary and environmen-tal factors.6,7 Hence, a molecule that targets not only fatty liver butother metabolic abnormalities such as dyslipidemia, hypertension, anddiabetes is needed to treat it holistically. Third, studies have shown thatexpression of Insig-1 also might be regulated by other PPAR iso-forms8,9; therefore, the molecule targeting a single gene (for example,PPAR�) has its own limitations. Fourth, the numerous differencesbetween mouse and human PPAR isoforms makes it imperative tofurther the research using human hepatic cell lines from patients withfatty liver. This will help the scientists, researchers, and clinicians toselect a few important drugs of great consequence for fatty liver fromthe vast armamentarium with significant therapeutic potential. Last,we think that a spirited and indomitable search for a potential therapyto treat all the correlated metabolic diseases based on the concept of thepolypill should be made.10,11

RAJEEV SHARMA1

PALLAWI TORKA2

1Department of Medicine, Metropolitan Hospital Centre, New YorkMedical College, New York, NY

2Department of Medicine, All India Institute of Medical Sciences, NewDelhi, India

References1. Qin X, Xie X, Fan Y, Tian J, Guan Y, Wang X, et al. Peroxisome proliferator-

activated receptor-delta induces insulin-induced gene-1 and suppresses hepaticlipogenesis in obese diabetic mice. HEPATOLOGY 2008;48:432-441.

2. Andrews DB, Schwimmer JB, Lavine JE. Fast break on the fat brake:mechanism of peroxisome proliferator-activated receptor-delta regulationof lipid accumulation in hepatocytes. HEPATOLOGY 2008;48:355-357.

3. Choi KC, Lee SY, Yoo HJ, Ryu OH, Lee KW, Kim SM, et al. Effect ofPPAR-delta agonist on the expression of visfatin, adiponectin, and resistin

in rat adipose tissue and 3T3–L1 adipocytes. Biochem Biophys Res Com-mun 2007;357:62-67.

4. Chen W, Wang LL, Liu HY, Long L, Li S. Peroxisome proliferator-activated receptor delta-agonist, GW501516, ameliorates insulin resis-tance, improves dyslipidaemia in monosodium L-glutamate metabolicsyndrome mice. Basic Clin Pharmacol Toxicol 2008;103:240-246.

5. Bloomgarden ZT. Second World Congress on the Insulin Resistance Syn-drome: insulin resistance syndrome and nonalcoholic fatty liver disease.Diabetes Care 2005;28:1518-1523.

6. Alberti KG, Zimmet P, Shaw J, the IDF Epidemiology Task Force Con-sensus Group. The metabolic syndrome: a new worldwide definition. Lan-cet 2005;366:1059-1062.

7. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Ameri-can Heart Association; National Heart, Lung, and Blood Institute. Defi-nition of metabolic syndrome: report of the National Heart, Lung, andBlood Institute/American Heart Association conference. Circulation2004;109:433-438.

8. Kast-Woelbern HR, Dana SL, Cesario RM, Sun L, de Grandpre LY,Brooks ME, et al. Rosiglitazone induction of Insig-1 in white adipose tissuereveals a novel interplay of peroxisome proliferator-activated receptor-�and sterol regulatory element-binding protein in the regulation of adipo-genesis. J Biol Chem 2004;279:23908-23915.

9. Konig B, Koch A, Spielmann J, Hilgenfeld C, Stangl GI, Eder K. Activa-tion of PPAR-� lowers synthesis and concentration of cholesterol by re-duction of nuclear SREBP-2. Biochem Pharmacol 2007;15:73:574-585.

10. Reddy KS. The preventive polypill: much promise, insufficient evidence.N Engl J Med 2007;356:212.

11. Kuehn BM. “Polypill” could slash diabetes risks. JAMA 2006;296:377-380.

Copyright © 2008 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.22602Potential conflict of interest: Nothing to report.

Reply:

Nonalcoholic fatty liver disease (NAFLD) is a potentially progres-sive liver disease associated with hepatic insulin resistance. Although acause-effect relationship between NAFLD and insulin resistance hasnot yet been confirmed, it is generally accepted that NAFLD is ahepatic component of the metabolic syndrome and an independentrisk factor for the development of type 2 diabetes.1,2 Several therapeu-tic approaches such as antioxidants, insulin sensitizers, and lipid-low-ering agents have been tested for the treatment of NAFLD. Althougha weight-reducing diet in overweight patients has proved effective, notherapeutic regime has proven effective to date.3 In our recent article“Peroxisome Proliferator-Activated Receptor-delta Induces Insulin-Induced Gene-1 and Suppresses Hepatic Lipogenesis in Obese Dia-betic Mice,” we demonstrated that peroxisome proliferator-activatedreceptor-� (PPAR-�) suppressed the activation of sterol regulatory el-ement-binding protein-1 via transactivation of insulin-induced gene-1and consequently reduced lipogenesis in cultured human hepatocytesas well as in the liver of obese diabetic mice.4 These results revealed anovel mechanism by which PPAR-� regulates lipid metabolism. Fol-lowing the publication of our article, Sharma et al. expressed theirinterest and concern about transforming the results from basic researchinto clinical practice.

We generally agree with the comment from Sharma et al. that theresults from basic research have to be translated into clinical practicewith caution. They note that targeting a single PPAR-� gene has alimitation, because the metabolic syndrome is an outcome of complexinteraction between numerous hereditary and environmental factorsand thus needs to be treated holistically. This is in line with the concept

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