van der Veen Jelske N, Lingrell Susanne, Gao Xia, Quiroga Ariel D, Takawale Abhijit, Armstrong Edward A, Yager Jerome Y, Kassiri Zamaneh, Lehner Richard, Vance Dennis E, Jacobs René L
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
Am J Physiol Gastrointest Liver Physiol. 2016 Apr 1;310(7):G526-38. doi: 10.1152/ajpgi.00243.2015. Epub 2016 Jan 21.
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.
磷脂酰乙醇胺N-甲基转移酶（PEMT）是肝脏磷脂酰胆碱（PC）生物合成中的一种重要酶。Pemt（-/-）小鼠可免受高脂饮食（HFD）诱导的肥胖和胰岛素抵抗；然而，这些小鼠会发展为非酒精性脂肪性肝病（NAFLD）。我们推测，吡格列酮激活过氧化物酶体增殖物激活受体γ（PPARγ）可能会刺激脂肪细胞增殖，从而将肝脏中的脂质导向白色脂肪组织。吡格列酮也可能直接作用于肝脏中的PPARγ以改善NAFLD。将Pemt（+/+）和Pemt（-/-）小鼠喂食含或不含吡格列酮（20mg·kg（-1）·天（-1））的HFD 10周。Pemt（-/-）小鼠免受HFD诱导的肥胖，但发展为NAFLD。吡格列酮治疗导致Pemt（-/-）小鼠体重增加，这主要归因于肥胖增加。此外，吡格列酮改善了Pemt（-/-）小鼠的NAFLD，肝脏重量减少35%和血浆丙氨酸转氨酶水平降低57%表明了这一点。喂食HFD的Pemt（-/-）小鼠的肝脏出现脂肪变性、炎症和纤维化。吡格列酮治疗的Pemt（-/-）小鼠肝脏中脂肪变性仍然明显；然而，吡格列酮治疗减少了肝纤维化，如天狼星红染色减少和Iα1型胶原（Col1a1）、金属蛋白酶组织抑制剂1（Timp1）、α-平滑肌肌动蛋白（Acta2）和转化生长因子-β（Tgf-β）的mRNA水平降低所证明。同样，吡格列酮治疗后，Pemt（-/-）小鼠肝脏中的氧化应激和炎症减少。总之，这些数据表明，喂食HFD的Pemt（-/-）小鼠中PPARγ的激活改善了肝功能，而这些小鼠仍然免受饮食诱导的肥胖和胰岛素抵抗。
