Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes
Jinsoo Song,
In-Jeoung Baek,
Sujeong Park,
Jinjoo Oh,
Deokha Kim,
Kyung Song,
Mi Kyung Kim,
Hye Won Lee,
Byoung Kuk Jang,
Eun-Jung Jin
Affiliations
Jinsoo Song
Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea; Integrated Omics Institute, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
In-Jeoung Baek
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
Sujeong Park
Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
Jinjoo Oh
Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
Deokha Kim
Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
Kyung Song
Department of Pharmacy, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
Mi Kyung Kim
Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
Hye Won Lee
Department of Pathology, Keimyung University School of Medicine, Daegu 42601, Korea
Byoung Kuk Jang
Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
Eun-Jung Jin
Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea; Integrated Omics Institute, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea; Corresponding author
Summary: 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 PPARγ resulting in the activation of PPARγ 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 PPARγ activation.
