Potential conflict of interest: Nothing to report.
Peroxisome proliferator–activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice†
Article first published online: 3 NOV 2008
Copyright © 2008 American Association for the Study of Liver Diseases
Volume 48, Issue 6, page 2085, December 2008
How to Cite
Sharma, R. and Torka, P. (2008), Peroxisome proliferator–activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology, 48: 2085. doi: 10.1002/hep.22602
- Issue published online: 24 NOV 2008
- Article first published online: 3 NOV 2008
To the Editor:
We read with interest the article by Qin et al.1 and the editorial comments by Andrews et al.2 regarding an elegantly revealed novel mechanism by which peroxisome proliferator-activated receptor-δ (PPARδ) regulates lipogenesis and suggesting its potential therapeutic use in liver steatosis or more appropriately non-alcoholic fatty liver disease. The authors strongly demonstrated that treatment with GW0742, the PPARδ agonist, or PPARδ overexpression markedly reduced intracellular lipid accumulation in the hepatocytes. The mechanism offered by them is that PPARδ acts by suppressing sterol regulatory element-binding protein-1 (SREBP-1) activity and by inducing the expression of insulin-induced gene-1 (Insig-1).1 The up-regulation of Insig-1 reduces lipid synthesis by preventing SREBPs from entering the Golgi apparatus for proteolytic generation of their transcriptionally active forms, thereby limiting the induction of SREBP target genes and hence lipid synthesis.
The role of PPARδ agonists in reducing body fat has been studied by various investigators. In a study by Choi et al.,3 it was shown that in the visceral adipose tissue of PPARδ agonist (L-165041)–treated rats, visfatin and adiponectin messenger RNA levels are significantly increased, suggesting that the PPARδ agonist has regulatory effects on a variety of adipokines. Similarly, another PPARδ agonist, GW501516, has been envisioned as a useful strategy against human metabolic syndrome and related diseases.4
Although in this study the authors have shown interesting observations, as clinicians, in our opinion, data from basic research studies needs to be transformed into clinical practice with caution. First, the cause–effect relationship of fatty liver and insulin resistance has been a matter of debate.5 Second, the metabolic syndrome is the outcome of a complex interaction between numerous hereditary and environmental factors.6, 7 Hence, a molecule that targets not only fatty liver but other metabolic abnormalities such as dyslipidemia, hypertension, and diabetes is needed to treat it holistically. Third, studies have shown that expression of Insig-1 also might be regulated by other PPAR isoforms8, 9; therefore, the molecule targeting a single gene (for example, PPARδ) has its own limitations. Fourth, the numerous differences between mouse and human PPAR isoforms makes it imperative to further the research using human hepatic cell lines from patients with fatty liver. This will help the scientists, researchers, and clinicians to select a few important drugs of great consequence for fatty liver from the vast armamentarium with significant therapeutic potential. Last, we think that a spirited and indomitable search for a potential therapy to treat all the correlated metabolic diseases based on the concept of the polypill should be made.10, 11
- 1Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. HEPATOLOGY 2008; 48: 432–441., , , , , , et al.
- 2Fast break on the fat brake: mechanism of peroxisome proliferator-activated receptor-delta regulation of lipid accumulation in hepatocytes. HEPATOLOGY 2008; 48: 355–357., , .
- 3Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3–L1 adipocytes. Biochem Biophys Res Commun 2007; 357: 62–67., , , , , , et al.
- 4Peroxisome proliferator-activated receptor delta-agonist, GW501516, ameliorates insulin resistance, improves dyslipidaemia in monosodium L-glutamate metabolic syndrome mice. Basic Clin Pharmacol Toxicol 2008; 103: 240–246., , , , .
- 5Second World Congress on the Insulin Resistance Syndrome: insulin resistance syndrome and nonalcoholic fatty liver disease. Diabetes Care 2005; 28: 1518–1523..
- 6IDF Epidemiology Task Force Consensus Group. The metabolic syndrome: a new worldwide definition. Lancet 2005; 366: 1059–1062., , , the
- 7American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference. Circulation 2004; 109: 433–438., , , , .
- 8Rosiglitazone induction of Insig-1 in white adipose tissue reveals a novel interplay of peroxisome proliferator-activated receptor-γ and sterol regulatory element-binding protein in the regulation of adipogenesis. J Biol Chem 2004; 279: 23908–23915., , , , , , et al.
- 9Activation of PPAR-α lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2. Biochem Pharmacol 2007; 15: 73: 574–585., , , , , .
- 10The preventive polypill: much promise, insufficient evidence. N Engl J Med 2007; 356: 212..
- 11“Polypill” could slash diabetes risks. JAMA 2006; 296: 377–380..
Rajeev Sharma*, Pallawi Torka, * Department of Medicine, Metropolitan Hospital Centre, New York Medical College, New York, NY, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.