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AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.

Artikel i vetenskaplig tidskrift
Författare Nikolaos Nikolaou
Laura L Gathercole
Lea Marchand
Sara Althari
Niall J Dempster
Charlotte J Green
Martijn van de Bunt
Catriona McNeil
Anastasia Arvaniti
Beverly A Hughes
Bruno Sgromo
Richard S Gillies
Hanns-Ulrich Marschall
Trevor M Penning
John Ryan
Wiebke Arlt
Leanne Hodson
Jeremy W Tomlinson
Publicerad i Metabolism: clinical and experimental
Volym 99
Sidor 67-80
ISSN 1532-8600
Publiceringsår 2019
Publicerad vid Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 67-80
Språk en
Länkar dx.doi.org/10.1016/j.metabol.2019.1...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Gastroenterologi

Sammanfattning

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.

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