Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes

Here, we found that heterozygous null of peroxisomal Nudt7 (Nudt7(+/-) induced the typical NAFLD features, i.e. increased levels of hepatic triglyceride (TG) and fatty acid (FA), infiltration of inflammatory cells, impaired glucose tolerance and insulin sensitivity, and stimulation of lipolysis from adipose tissue. Particularly, in Nudt7(+/-) hepatocytes, de novo lipogenesis (DNL) was significantly increased. Ingenuity pathway analysis (IPA) and KEGG pathway analysis of RNA sequencing data suggested the activation of PPAR signaling in the liver of Nudt7(+/-) mice. Moreover, accumulation of palmitic acid in Nudt7(+/-) hepatocyte increased the level of H3K4me3 on the promoters of PPAR gamma resulting in the activation of PPAR gamma and induced the DNL in the hepatocytes of Nudt7(+/-) mice. Moreover, we found that liraglutide significantly reduced typical NAFLD features induced by NUDT7 deficiency. Our data suggest that dysregulation of peroxisomal NUDT7 is responsible for upregulation of hepatic DNL by accumulation of palmitic acid and PPAR gamma activation.

Automated summary

The aberrant expression of peroxisomal NUDT7 leads to typical features of non-alcoholic fatty liver disease, including increased levels of hepatic triglycerides and fatty acids, infiltration of inflammatory cells, impaired glucose tolerance and insulin sensitivity, and stimulation of adipose tissue lipolysis. The deficiency of Nudt7 enhances de novo lipogenesis in hepatocytes and activates PPAR signaling pathway. Liraglutide can reduce the typical features of non-alcoholic fatty liver disease caused by NUDT7 deficiency.