AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.
5β-Reductase
Bile acids
Diabetes
FXR
NAFLD
Triglyceride
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
10
05
2019
revised:
28
06
2019
accepted:
18
07
2019
pubmed:
23
7
2019
medline:
20
2
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31330134
pii: S0026-0495(19)30144-1
doi: 10.1016/j.metabol.2019.153947
pmc: PMC6744372
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
RNA, Messenger
0
Oxidoreductases
EC 1.-
3-oxo-5 beta-steroid delta 4-dehydrogenase
EC 1.3.99.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
67-80Subventions
Organisme : British Heart Foundation
ID : FS/15/56/31645
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U142661184
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P011462/1
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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