Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-(PEMT) deficient mice.

VAN DER VEEN, J; LINGRELL, S; GAO, X; QUIROGA, ARIEL DARIO; TAKAWALE, A; ARMSTRONG, EA; YAGER, JY; KASSIRI, Z; LEHNER R; VANCE, DE; JACOBS, RL

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

AMER PHYSIOLOGICAL SOC

Lugar: Bethesda; Año: 2015

0193-1857

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Mice that lack PEMT are protected against high-fat diet-induced obesity and insulin resistance; however, these mice develop non-alcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator activated receptor (PPAR)γ activation by pioglitazone might stimulate adipocyte proliferation thereby directing lipids from the liver towards white adipose tissue. Pioglitazone might also act directly on the PPARγ in liver to improve NAFLD. Pemt+/+ and Pemt-/- mice were fed a high-fat diet with or without pioglitazone (20 mg/kg/day) for 10 weeks. Pemt-/- mice were protected from high-fat diet-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 (ALT) levels. Livers from Pemt-/- mice fed the high-fat diet 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 collagen1a1 (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 PEMT-deficient livers upon treatment with pioglitazone. Together, these data show that activating PPARγ in high-fat diet-fed Pemt-/- mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology.