Anti‐adipogenic action of pitavastatin occurs through the coordinate regulation of PPARγ and Pref‐1 expression

Adipocyte differentiation in vitro is coordinately activated by two transcription factors, peroxisome proliferator‐activated receptor γ (PPARγ) and CCAAT enhancer binding protein α (C/EBPα), but it is inhibited by preadipocyte factor‐1 (pref‐1). Statins, inhibitors of HMG‐CoA reductase and de novo cholesterol synthesis, can have pleiotropic effects which influence adipocyte phenotype by ill‐defined mechanisms. We investigated the effects of pitavastatin (NK‐104) on adipocyte differentiation and the transcriptional pathways involved.

[1]  H. Green,et al.  Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line , 1979, Journal of cellular physiology.

[2]  O. Rosen,et al.  Organelle relationships in cultured 3T3-L1 preadipocytes , 1980, The Journal of cell biology.

[3]  D. Bernlohr,et al.  Evidence for an increase in transcription of specific mRNAs during differentiation of 3T3-L1 preadipocytes. , 1985, Journal of Biological Chemistry.

[4]  H. Green,et al.  The nucleotide sequence of three genes participating in the adipose differentiation of 3T3 cells. , 1986, The Journal of biological chemistry.

[5]  J. Flier,et al.  Insulin resistance--mechanisms, syndromes, and implications. , 1991, The New England journal of medicine.

[6]  M. Lane,et al.  Antisense CCAAT/enhancer-binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 preadipocytes. , 1992, Genes & development.

[7]  M. Rao,et al.  Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. , 1993, The Journal of biological chemistry.

[8]  H. Sul,et al.  Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation , 1993, Cell.

[9]  B. Spiegelman,et al.  Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. , 1993, The Journal of biological chemistry.

[10]  S. Freytag,et al.  Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. , 1994, Genes & development.

[11]  O. MacDougald,et al.  Regulation of adipocyte development. , 1994, Annual review of nutrition.

[12]  J. Lehmann,et al.  A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation , 1995, Cell.

[13]  S. McKnight,et al.  Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. , 1995, Genes & development.

[14]  J. Lehmann,et al.  Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. , 1996, Molecular pharmacology.

[15]  H. Nakata,et al.  3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor impairs cell p4fferentiation in cultured adipogenic cells (3T3-L1). , 1996, European journal of pharmacology.

[16]  M. Lazar,et al.  Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription , 1997, Molecular and Cellular Biology.

[17]  J. Gimble,et al.  CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. , 1997, Biochemical and biophysical research communications.

[18]  J. Northrop,et al.  TNFα-Mediated Inhibition and Reversal of Adipocyte Differentiation Is Accompanied by Suppressed Expression of PPARγ without Effects on Pref-1 Expression. , 1997, Endocrinology.

[19]  Cleavage of membrane-associated pref-1 generates a soluble inhibitor of adipocyte differentiation. , 1997, Molecular and cellular biology.

[20]  M. Lazar,et al.  Peroxisome Proliferator Activated Receptor γ, CCAAT/ Enhancer-binding Protein α, and Cell Cycle Status Regulate the Commitment to Adipocyte Differentiation* , 1997, The Journal of Biological Chemistry.

[21]  S. Mandrup,et al.  Regulating Adipogenesis* , 1997, The Journal of Biological Chemistry.

[22]  B. Spiegelman.  PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. , 1998, Diabetes.

[23]  H. Sul,et al.  Understanding adipocyte differentiation. , 1998, Physiological reviews.

[24]  M. Moreno-Aliaga,et al.  Endrin inhibits adipocyte differentiation by selectively altering expression pattern of CCAAT/enhancer binding protein-alpha in 3T3-L1 cells. , 1999, Molecular pharmacology.

[25]  H. Sul,et al.  Transcriptional Repression of pref-1 by Glucocorticoids Promotes 3T3-L1 Adipocyte Differentiation* , 1999, The Journal of Biological Chemistry.

[26]  X. Xia,et al.  Inhibition of adipose differentiation by phosphatidylinositol 3-kinase inhibitors. , 1999, Journal of cellular physiology.

[27]  M. Lane,et al.  Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiation. , 1999, Biochemical and biophysical research communications.

[28]  B. Spiegelman,et al.  A Synthetic Antagonist for the Peroxisome Proliferator-activated Receptor γ Inhibits Adipocyte Differentiation* , 2000, The Journal of Biological Chemistry.

[29]  S. Kurebayashi,et al.  TNF-α Inhibits 3T3-L1 Adipocyte Differentiation without Downregulating the Expression of C/EBPβ and δ , 2001 .

[30]  J. Larosa,et al.  Pleiotropic effects of statins and their clinical significance. , 2001, American Journal of Cardiology.

[31]  J. Liao,et al.  Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[32]  H. Linhart,et al.  C/EBPα is required for differentiation of white, but not brown, adipose tissue , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  H. Sul,et al.  Only the large soluble form of preadipocyte factor-1 (Pref-1), but not the small soluble and membrane forms, inhibits adipocyte differentiation: role of alternative splicing. , 2002, The Biochemical journal.

[34]  H. Sul,et al.  Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity , 2002, Molecular and Cellular Biology.

[35]  M. Kasuga,et al.  Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. , 2002, Diabetes.

[36]  Chunli Song,et al.  Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. , 2003, Biochemical and biophysical research communications.

[37]  A. Gotto,et al.  Adipogenic differentiating agents regulate expression of fatty acid binding protein and CD36 in the J744 macrophage cell line Published, JLR Papers in Press, July 16, 2003. DOI 10.1194/jlr.M300084-JLR200 , 2003, Journal of Lipid Research.

[38]  Gwo‐Jaw Wang,et al.  Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARgamma2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures. , 2003, Bone.

[39]  H. Sul,et al.  Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). , 2003, The Journal of clinical investigation.

[40]  Maia M. Jack,et al.  Adiponectin gene activation by thiazolidinediones requires PPARγ2, but not C/EBPα—evidence for differential regulation of the aP2 and adiponectin genes , 2003 .

[41]  A. Gotto,et al.  Functional Interplay Between the Macrophage Scavenger Receptor Class B Type I and Pitavastatin (NK-104) , 2004, Circulation.

[42]  M. Nakata,et al.  Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control , 2006, Diabetologia.

[43]  S. Farmer.  Transcriptional control of adipocyte formation. , 2006, Cell metabolism.

[44]  O. MacDougald,et al.  Adipocyte differentiation from the inside out , 2006, Nature Reviews Molecular Cell Biology.

[45]  H. Sul,et al.  Pref-1 (Preadipocyte Factor 1) Activates the MEK/Extracellular Signal-Regulated Kinase Pathway To Inhibit Adipocyte Differentiation , 2006, Molecular and Cellular Biology.

[46]  H. Sul,et al.  Preadipocyte factor-1 (Pref-1) Activates MEK/ ERK Pathway To Inhibit Adipocyte , 2007 .