title: Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice.
abstract: Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt(-/-) mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt(+/+) and Pemt(-/-) mice were fed a HFD with or without pioglitazone (20 mg·kg(-1)·day(-1)) for 10 wk. Pemt(-/-) mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt(-/-) mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt(-/-) mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt(-/-) mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt(-/-) mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 (Col1a1), tissue inhibitor of metalloproteinases 1 (Timp1), α-smooth muscle actin (Acta2), and transforming growth factor-β (Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt(-/-) mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt(-/-) mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Jelske N
authors.initials: JN
authors.lastname: van der Veen
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Susanne
authors.initials: S
authors.lastname: Lingrell
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Ariel D
authors.initials: AD
authors.lastname: Quiroga
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Edward A
authors.initials: EA
authors.lastname: Armstrong
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Jerome Y
authors.initials: JY
authors.lastname: Yager
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Richard
authors.identifier: 0000-0002-6008-1805
authors.initials: R
authors.lastname: Lehner
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada rjacobs@ualberta.ca.
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D052438:Adipocytes, White / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D059305:Diet, High-Fat; D020022:Genetic Predisposition to Disease; D006505:Hepatitis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010641:Phenotype; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D000890:Anti-Infective Agents; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D047495:PPAR gamma; D045162:Thiazolidinediones; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D000077205:Pioglitazone
keywords: fibrosis; nonalcoholic fatty liver disease; peroxisomal proliferator-activated receptor-γ; phosphatidylcholine; steatohepatitis