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Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

Artikel i vetenskaplig tidskrift
Författare Manoj Amrutkar
M. Kern
Esther Nuñez Durán
Marcus Ståhlman
Emmelie Cansby
Urszula Chursa
Elin Stenfeldt
Jan Borén
M. Bluher
Margit Mahlapuu
Publicerad i Diabetologia
Volym 59
Nummer/häfte 2
Sidor 341-353
ISSN 0012-186X
Publiceringsår 2016
Publicerad vid Wallenberglaboratoriet
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 341-353
Språk en
Länkar dx.doi.org/10.1007/s00125-015-3801-...
Ämnesord Ectopic lipid storage, Insulin resistance, Lipid droplets, Liver lipid metabolism, hepatic insulin-resistance, triacylglycerol lipase, triglyceride lipase, adipose-tissue, tca cycle, disease, metabolism, steatosis, loci, mice, Endocrinology & Metabolism
Ämneskategorier Endokrinologi och diabetes

Sammanfattning

Aims/hypothesis Type 2 diabetes is closely associated with pathological lipid accumulation in the liver, which is suggested to actively contribute to the development of insulin resistance. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of liver steatosis, whole-body glucose tolerance and insulin sensitivity in a mouse model system. The aim of this study was to assess the role of STK25 in the control of lipid metabolism in human liver. Methods Intracellular fat deposition, lipid metabolism and insulin sensitivity were studied in immortalised human hepatocytes (IHHs) and HepG2 hepatocellular carcinoma cells in which STK25 was overexpressed or knocked down by small interfering RNA. The association between STK25 mRNA expression in human liver biopsies and hepatic fat content was analysed. Results Overexpression of STK25 in IHH and HepG2 cells enhanced lipid deposition by suppressing beta-oxidation and triacylglycerol (TAG) secretion, while increasing lipid synthesis. Conversely, knockdown of STK25 attenuated lipid accumulation by stimulating beta-oxidation and TAG secretion, while inhibiting lipid synthesis. Furthermore, TAG hydrolase activity was repressed in hepatocytes overexpressing STK25 and reciprocally increased in cells with STK25 knockdown. Insulin sensitivity was reduced in STK25-overexpressing cells and enhanced in STK25-deficient hepatocytes. We also found a statistically significant positive correlation between STK25 mRNA expression in human liver biopsies and hepatic fat content. Conclusions/interpretation Our data suggest that STK25 regulates lipid partitioning in human liver cells by controlling TAG synthesis as well as lipolytic activity and thereby NEFA release from lipid droplets for beta-oxidation and TAG secretion. Our findings highlight STK25 as a potential drug target for the prevention and treatment of type 2 diabetes.

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