Dysregulation of Δ 4 -3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms

Valanejad, Leila; Ghareeb, Mwlod; Shiffka, Stephanie J.; Nadolny, Christina; Chen, Yuan; Guo, Le‐Hang; Verma, Ruchi; You, Sangmin; Akhlaghi, Fatemeh; Deng, Ruitang

doi:10.1016/j.mce.2017.10.005

Cited by 22 publications

(20 citation statements)

References 56 publications

(85 reference statements)

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“…The MRP3 mRNA expression levels were significantly elevated in patients with NAFLD, especially with NASH, compared to the healthy control subjects [94]. In another study with diabetic patients, MRP3 and MRP4 expression levels were not significantly altered in diabetic patients compared to control subjects [106]. Taken together, the results from limited studies suggest that MRP3 and MRP4 were upregulated in patients with NAFLD, while the effects of NAFLD on MRP2 expression were minimal.…”

Section: Mrpsmentioning

confidence: 83%

“…and control subjects [106]. In summary, NTCP expression was likely upregulated in NAFLD patients with certain inconsistency.…”

Section: Enterohepatic Circulation Of Bile Acids Through a Series Of mentioning

confidence: 84%

“…Both OATP1B1 and OATP1B3 mRNA expression levels were significantly upregulated in patients with NAFLD compared to control subjects [101]. In a different study with diabetic patients, the expression levels of OATP1B1 were comparable in diabetic patients compared to control subjects [106]. Therefore, it can be cautiously concluded that OATP1B1 and OATP1b3 expression were largely induced in patients with NAFLD.…”

Section: Oatpsmentioning

confidence: 88%

“…In one study with NAFLD and one study with diabetic patients, MRP2 mRNA expression levels were not significantly altered in NAFLD and diabetic patients compared to control subjects [88,106]. Another study reported that MRP2 mRNA expression levels were decreased as the NAFLD progressed from steatosis to NASH [122].…”

Section: Mrpsmentioning

confidence: 95%

“…A different study reported that BSEP mRNA expression levels were increased in patients with NASH compared to the patients with simple steatosis [118]. On the other hand, two studies revealed that BSEP mRNA expression was not altered in patients with NAFLD or diabetes compared to healthy control subjects [101,106]. Finally, another study reported that BSEP mRNA levels were elevated in lean NAFLD patients but reduced in overweight or obese patients with steatosis or NASH [94], indicating that body weight of the patients influences the expression of BSEP under the NAFLD condition.…”

Section: Bsepmentioning

confidence: 99%

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Dysregulation of Bile Acids in Patients with NAFLD

Zhang¹,

Deng²

2019

Nonalcoholic Fatty Liver Disease - An Update

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Bile acids are synthesized in the liver and tightly regulated through the enterohepatic circulation. Recent studies reveal that bile acids serve as hormone-like signaling molecules to activate nuclear receptors, notably farnesoid X receptor (FXR), regulating metabolic homeostasis of bile acids, cholesterol, lipids, and glucose. A connection between bile acids and nonalcoholic fatty liver disease (NAFLD) has long been recognized. Although inconsistent or even contradictory results are reported, a large body of evidence from clinical as well as preclinical studies demonstrates that bile acid homeostasis is disrupted in patients with NAFLD. The bile acid dysregulation gets worsening as NAFLD progresses from early stage simple steatosis to late stage nonalcoholic steatohepatitis (NASH) and NASH with fibrosis. As the risk factors for NAFLD, obesity and insulin resistance, which are often associated with NAFLD, contribute to the dysregulation of bile acids in patients with NAFLD. Total serum and fecal bile acid concentrations are mostly elevated in patients with NAFLD as a result of increased bile acid synthesis, elevated hepatic bile acids, and upregulation of bile acid transporters. The two negative feedback regulatory pathways for bile acid synthesis, FXR/SHP (small heterodimer partner) and fibroblast growth factor-19 (FGF19)/FGF receptor-4 (FGFR4), are impaired in patients with NAFLD.

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Section: Mrpsmentioning

confidence: 83%

“…and control subjects [106]. In summary, NTCP expression was likely upregulated in NAFLD patients with certain inconsistency.…”

Section: Enterohepatic Circulation Of Bile Acids Through a Series Of mentioning

confidence: 84%

Section: Oatpsmentioning

confidence: 88%

Section: Mrpsmentioning

confidence: 95%

Section: Bsepmentioning

confidence: 99%

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Dysregulation of Bile Acids in Patients with NAFLD

Zhang¹,

Deng²

2019

Nonalcoholic Fatty Liver Disease - An Update

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AKR1D1 regulates glucocorticoid availability and glucocorticoid receptor activation in human hepatoma cells

Νικολάου

Gathercole

Kirkwood

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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Steroid hormones, including glucocorticoids and androgens, have potent actions to regulate many cellular processes within the liver. The steroid A-ring reductase, 5β-reductase (AKR1D1), is predominantly expressed in the liver, where it inactivates steroid hormones and, in addition, plays a crucial role in bile acid synthesis. However, the precise functional role of AKR1D1 to regulate steroid hormone action in vitro has not been demonstrated. We have therefore hypothesised that genetic manipulation of AKR1D1 has the potential to regulate glucocorticoid availability and action in human hepatocytes.

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