Abstract
Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt−/− mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt−/− mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has been widely recognized as an important manifestation of metabolic syndrome and the development of non-alcoholic steatohepatitis (NASH) is closely related to the obesity and insulin resistance[1]
The PC/PE ratio is a key regulator of cell membrane integrity and a disturbance in the ratio plays an important role in the progression of steatosis to steatohapatitis under choline-deficient diet[31]
The liver is mainly involved in determining their phenotype and the activity of Pemt is relatively lower in adipose tissues, the conversion of PE to PC in adipocytes appears to be important for the stabilization of lipid droplets and normal fat distribution[33]
Summary
Pemt deficiency resists to diet-induced obesity and insulin resistance. At 25 weeks of age, the diet-induced bogy weight gain observed in Pemt+ /+ and Pemt+ /− mice fed HFHS chow was completely reversed in Pemt− /− mice to the levels of the mice fed STD chow (Supplementary Fig. 1a). In Pemt− /− mice fed HFHS chow, the expression of cleaved caspase 3, 7 and Bax protein prominently increased (Fig. 4a), and the number of TUNEL-positive apoptotic cells significantly increased in Pemt− /− mice compared to Pemt+ /+ mice fed HFHS chow (Fig. 4b,c). High glucose and IL-6 did not affect the expression of cleaved caspase 3 and 7, and phosphorylation of Akt. prominent apoptosis in hepatocytes was characteristic features in the liver of Pemt− /− mice fed HFHS chow, the number of Ki67-positive hepatocyte increased in Pemt− /− mice compared to Pemt+ /+ mice fed HFHS diet (Fig. 5a,b). The protein expression of F-box protein 31 (Fbxo31) and hepatocyte nuclear factor 4 alpha (HNF4α ) decreased in Pemt− /− fed HFHS compared with Pemt+ /+ mice (Fig. 8c). Lower quartile of PEMT mRNA (Q2) demonstrated lower BMI and platelet counts (Supplementary Fig. 10), suggesting lower expression of PEMT mRNA is related to the development of lean NASH
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