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Biochemical and biophysical research communications v.494 no.3/4, 2017년, pp.460 - 469   SCI SCIE
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Dihydroceramide is a key metabolite that regulates autophagy and promotes fibrosis in hepatic steatosis model

Lee, Ah Young (Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea ); Lee, Jae Won (Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin 17104, Republic of Korea ); Kim, Ji-Eun (Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea ); Mock, Hyuck Jun (Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin 17104, Republic of Korea ); Park, Sungjin (Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea ); Kim, Sanghwa (Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea ); Hong, Seong-Ho (Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul ); Kim, Ji-Young ( ); Park, Eun-Jung ( ); Kang, Kyung-Sun ( ); Kim, Kwang Pyo ( ); Cho, Myung-Haing ( );
  • 초록  

    Abstract Non-alcoholic fatty liver disease (NAFLD) is an increasingly common chronic liver disease worldwide. Sphingolipids are a family of lipids that play essential roles as critical regulators in metabolic disorders. Some sphingolipids are known key factors in metabolic dysfunction. However, the precise effect of dihydroceramide on NAFLD remains unknown. Here, we report how dihydroceramide in autophagosome accumulation activates fibrogenesis in human liver Chang cells treated with free fatty acids (FFA). According to LC/MS lipid profiling, FFA increased the levels of sphingolipids and triacylglycerol (TG). To demonstrate the potential role of dihydroceramide metabolism in autophagy, several sphingolipid synthesis inhibitors were used. Increased dihydroceramide led to impairment of autophagic flux, resulting in increased TG storage in lipid droplets (LD) and upregulated expression of fibrosis markers. Hepatic stellate cells (HSCs, LX-2 cells) were co-cultured with Chang cells to assess the potential fibrogenic response to dihydroceramide, Treatment with rapamycin recovered autophagic flux in Chang cells and fibrogenesis in the co-culture system. Our results identified a critical function of dihydroceramide metabolism in autophagy. It could play an important role in the progression of NAFLD associated with lipid over-accumulation. Therefore, preventing autophagic flux by regulating dihydroceramide could be a potential strategic approach for providing therapy for NAFLD. Highlights FFA uptake increases sphingolipids in liver cells. Dihydroceramide product correlates with autophagosome accumulation. Dihydroceramide impairs autophagic flux and increases lipid droplets. Rapamycin recuperates fibrosis by recovering autophagic flux by increased dihydroceramide.


  • 주제어

    Dihydroceramide .   Autophagy .   NAFLD .   Fibrosis .   Fatty acid/Metabolism .   Sphingolipids.  

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