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

Νικολάου, Νικόλαος; Gathercole, Laura; Marchand, Lea; Althari, Sara; Dempster, Niall; Green, Charlotte; Bunt, Martijn van de; McNeil, Catriona; Arvaniti, Anastasia; Hughes, Beverly; Sgromo, Bruno; Gillies, Richard; Marschall, Hanns‐Ulrich; Penning, T.M.; Ryan, John D.; Arlt, Wiebke; Hodson, Leanne; Tomlinson, Jeremy

doi:10.1016/j.metabol.2019.153947

Cited by 60 publications

(65 citation statements)

References 69 publications

(62 reference statements)

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“…Recently, changes in the expression patterns of transcriptional regulators and downstream target genes have been associated with the development and progression of chronic liver diseases such as NAFLD [65,66], non-alcoholic steatohepatitis (NASH) [67], fibrosis [15] and human hepatocellular carcinoma (HCC) [54]. Here we show that our methodology is highly sensitive to detect those gene markers in the nuclear transcriptome ( Fig.…”

Section: Snrna-seq2 Uncovers Transcription Factors and Rate Limiting mentioning

confidence: 62%

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“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

Richter

Deligiannis

Danese

et al. 2020

Preprint

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Single-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity we have developed a single-nucleus RNA-seq-2 method that allows deep characterization of nuclei isolated from frozen archived tissues. We have used this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobe. Our work has revealed a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes.

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Section: Snrna-seq2 Uncovers Transcription Factors and Rate Limiting mentioning

confidence: 62%

“…2E-F). In particular, dysregulation of Akr1d1 has been associated with human NAFLD [66], and upregulation of Wwtr1 (also known as TAZ) in human and murine NASH liver [68]. Furthermore, Tead1 has been proposed as a marker of NASH in murine mouse models [69].…”

Section: Snrna-seq2 Uncovers Transcription Factors and Rate Limiting mentioning

confidence: 99%

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

Richter

Deligiannis

Danese

et al. 2020

Preprint

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“…4C). Relevant to lipid metabolism, we found upregulation of three genes related to cholesterol transport (NR0B2 39 , APOA4 40 , and APOA1 41 ) and another seven genes related to cholesterol biosynthesis (MVK, MVD, HMGCS1 42 , FDFT1 43 , HMGCR 44 , FDPS 45 , CYP51A1 46 ), along with downregulation of AKR1D1 47 , involved in cholesterol catabolism (Fig. 3a).…”

Section: Ethanol-induced Steatosis In the Liver-chipmentioning

confidence: 89%

Modeling alcoholic liver disease in a human Liver-Chip

Nawroth

et al. 2020

Preprint

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Fatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis and for the development of sensitive noninvasive diagnostics and therapies. Alcohol-induced liver disease (ALD) represents an ideal case for modeling FDL as ethanol exposure is a comparatively simpler trigger for experimental induction of the pathology, as opposed to the complexity of modeling the diet- and life-style induced FLD. Further, despite their different root causes several common characteristics in disease progression and deterioration of liver function in the two disease entities, highlighting the potential of an ALD microphysiological model for broad application in translational research. Here, we leverage our recently reported human Liver-Chip for toxicity applications, to expand the capabilities of the platform for broad application in translational research. We report the first in vitro modeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. Importantly, we show that the ALD Liver-Chip supports the study of secondary insults, as patients with advanced ALD often show high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, owing to new developments in the design, the ALD Liver-Chip enables the measurement of structural changes of the bile canaliculi (BC) network as a novel in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury with direct translation to clinical research.

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“…In addition, they are used in combination with anti-cancer agents to reduce the genotoxic side effects of chemotherapy treatment, including nausea and vomiting (Collins et al 2007; Buxant et al 2015). Pro-longed use of synthetic glucocorticoids is however associated with adverse metabolic effects including obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) (Woods et al 2015), and decreased AKR1D1 expression has been recently shown in patients with type 2 diabetes and NAFLD (Valanejad et al 2018; Nikolaou et al 2019b). Our study indicates that AKR1D1-002 is the predominant functional variant in human liver; alterations in AKR1D1-002 expression and activity may therefore contribute to the adverse metabolic impact of exogenous glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

Differential activity and expression of human 5β-reductase (AKR1D1) splice variants

Appanna

Gangitano

Dempster

et al. 2020

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30 31 32 Word count (excluding references and figure legends): 4319 33 34 35 36 Abstract 37Steroid hormones, including glucocorticoids and androgens, exert a wide variety of effects in 38 the body across almost all tissues. The steroid A-ring 5β-reductase (AKR1D1) is expressed in 39 human liver and testes, and three splice variants have been identified (AKR1D1-001, 40 AKR1D1-002, . Amongst these, AKR1D1-002 is the best described; it 41 modulates steroid hormone availability and catalyses an important step in bile acid synthesis. 42However, specific activity and expression of AKR1D1-001 and AKR1D1-006 are unknown. 43 44 AKR1D1-002, AKR1D1-001 and AKR1D1-006 were measured in human liver biopsies and 45 human hepatoma cell lines by qPCR. Three-dimensional (3D) structures of AKR1D1 variants 46 were determined using in silico approaches. AKR1D1 variants were over-expressed in 47 HEK293 cells, and successful overexpression confirmed by qPCR and western blotting. 48Steroid hormone clearance was measured by mass spectrometry and ELISA, and steroid 49 receptor activation determined by luciferase reporter assays. 50 51 AKR1D1-002 and AKR1D1-001 are expressed in human liver, and only AKR1D1-006 is 52 expressed in human testes. Following over-expression in HEK293 cells, AKR1D1-001 and 53 AKR1D1-006 protein levels were lower than AKR1D1-002, but significantly increased 54 following treatment with the proteasomal inhibitor, MG-132. AKR1D1-002 efficiently 55 metabolised glucocorticoids and androgens and decreased receptor activation. AKR1D1-001 56 and AKR1D1-006 poorly metabolised dexamethasone, but neither protein metabolised 57 cortisol, prednisolone or testosterone. 59We have demonstrated the differential expression and role of AKR1D1 splice variants to 60 regulate steroid hormone clearance and receptor activation. AKR1D1-002 is the predominant 61 functional protein in steroidogenic and metabolic tissues. In addition, AKR1D1-001 and 62 AKR1D1-006 may have a limited role in the regulation of synthetic glucocorticoid action. 63 64 Introduction 65Steroid hormones, including glucocorticoids, androgens and oestrogens, are fat-soluble 66 molecules synthesised from cholesterol that play a crucial role in development, differentiation 67 and metabolism (Simons 2008). Glucocorticoids, produced by the adrenal cortex, are released 68 in response to stress and, following binding to their cognate receptor, the glucocorticoid 69 receptor (GR), regulate anti-inflammatory and metabolic processes. Androgens are 70 predominantly produced by the male testes, but also by the adrenal glands and the ovaries in 71 females. Upon binding to the androgen receptor (AR), they have multiple actions, including 72 the initiation of adrenarche and stimulation and control of secondary sexual characteristics. 73Following synthesis and delivery into the circulation, steroid hormones can be reduced, 74 oxidised or hydroxylated by a variety of enzymes, including the 11β-hydroxysteroid 75 dehydrogenases (11β-HSD) and the Α-ring reductases (5α-reductases, [5αR] an...

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

Cited by 60 publications

References 69 publications

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

Modeling alcoholic liver disease in a human Liver-Chip

Differential activity and expression of human 5β-reductase (AKR1D1) splice variants

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