Evidence map›Paper›PMID 31330134›Full record

ArticleMetabolism: clinical and experimental2019

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

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 and 8 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Metabolism: clinical and experimental, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.

0numbers the graph read from it
0cells of the map it votes in
43citing papers in PubMed
6.5field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

43 citing papers in PubMed, 82 citations in OpenAlex.

  1. Trial
  2. Article
  3. Article
  4. Functional Role of COP1 Gene in Hepatocellular Carcinoma Lipid Metabolism and Stemness.Genes to cells : devoted to molecular & cellular mechanisms · 2026
    Article
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  20. Relevance of Human Aldoketoreductases and MicrobialDrug metabolism and disposition: the biological fate of chemicals · 2023
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 6 institutions in 3 countries.

Nikolaos NikolaouOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Laura L GathercoleOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Lea MarchandOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Sara AlthariOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Niall J DempsterOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Charlotte J GreenOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Martijn van de BuntOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Catriona McNeilOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Anastasia ArvanitiOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Beverly A HughesInstitute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Bruno SgromoDepartment of Upper GI Surgery, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Richard S GilliesDepartment of Upper GI Surgery, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Hanns-Ulrich MarschallDepartment of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden.
Trevor M PenningDepartment of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, 1315 BRB II/III 421 Curie Blvd, Philadelphia, PA 19104-6160, United States of America.
John RyanTranslational Gastroenterology Unit, University of Oxford, Oxford, UK.
Wiebke ArltInstitute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Leanne HodsonOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Jeremy W TomlinsonOxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK. Electronic address: jeremy.tomlinson@ocdem.ox.ac.uk.
Oxford Centre for Diabetes, Endocrinology and Metabolism · GBUniversity of Oxford · GBChurchill Hospital · GBUniversity of Birmingham · GBUniversity of Gothenburg · SEUniversity of Pennsylvania · US

Funding

Translational Research Support CoreP30ES013508 · NIEHS · UNIVERSITY OF PENNSYLVANIA · PI A. Clementina Mesaros · 2006 to 2026
$35.3M
British Heart Foundation FS/15/56/31645Medical Research Council MC_U142661184Medical Research Council MR/P011462/1NIEHS NIH HHS P30 ES013508
6 · The paper itself

Abstract

objectiveNon-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.

methodsHuman 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.

resultsIn 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.

conclusionsGenetic 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.

Indexed as

PhenotypeBile Acids and SaltsHepatocytesHep G2 CellsHumansInflammationNon-alcoholic Fatty Liver DiseaseObesityOxidoreductasesRNA, Messenger3-oxo-5 beta-steroid delta 4-dehydrogenaseBile Acids and SaltsOxidoreductasesRNA, Messenger5β-ReductaseBile acidsDiabetesFXRNAFLDTriglyceride

Identifiers

PMID31330134
PMCPMC6744372
OpenAlexW2964264888

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.