Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

doi:10.1038/srep28178

Cited by 72 publications

(61 citation statements)

References 54 publications

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“…In our current study, however, we consistently observed upregulation of PXR and CYP3A4 in high-glucose conditions and showed that the pharmacologic activation of AMPK robustly repressed glucose-induced PXR transcriptional activity. The discrepancy between our observations and those of Davidson et al 59. could be due to the differences in the experimental systems or cell types used (HepG2 cancer cells vs. primary hepatocytes).…”

Section: Discussioncontrasting

confidence: 99%

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Oladimeji

Lin

Brewer

et al. 2017

Sci Rep

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Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations. We observed that PXR activity was induced under high-glucose conditions. This finding is consistent with previous clinical reports of increased drug clearance in patients with untreated diabetes. We demonstrated that AMP-activated protein kinase (AMPK) modulates PXR transcriptional activity and that pharmacologically manipulated AMPK activation exhibits an inverse relation to PXR activity. Activation of AMPK was shown to downregulate PXR activity and, consistent with that, potentiate the response of cells to the drug. Taken together, our results delineate a hitherto unreported axis of regulation that involves the energy status of the cell, PXR regulation, and drug sensitivity.

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Section: Discussioncontrasting

confidence: 99%

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Oladimeji

Lin

Brewer

et al. 2017

Sci Rep

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“…Significantly higher (almost double) levels of hepatic cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) were found in patients in the high‐HIS group compared to the low‐HIS group (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1077/suppinfo). The enzymatic activity and expression level of CYP2C19 protein were reported to decrease with progression of NAFLD, and the expression level of its gene is reportedly influenced by the glycemic state . Further studies are needed to determine the therapeutic potential of CYP2C19 in NAFLD‐associated hepatic insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…The enzymatic activity and expression level of CYP2C19 protein were reported to decrease with progression of NAFLD, (51) and the expression level of its gene is reportedly influenced by the glycemic state. (52) Further studies are needed to determine the therapeutic potential of CYP2C19 in NAFLDassociated hepatic insulin resistance. Gene ontology analysis showed down-regulation of mRNA expression of genes involved in the oxidation-reduction process and inflammatory response in the high-HIS group ( Supporting Table S2), which may associate with the lower lobular inflammation score as assessed by liver histopathologic examination (P 5 0.06; Fig.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

Shigiyama

Kumashiro

Furukawa

et al. 2017

Hepatology Communications

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Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high‐HIS, mid‐HIS, low‐HIS), as assessed by the hyperinsulinemic‐euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high‐HIS group was identical to that of the non‐NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low‐HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high‐HIS and low‐HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis‐aconitic acid, were significantly higher in the high‐HIS group compared to the low‐HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin‐sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634–647)

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“…Khetani and Bhatia have demonstrated that 3T3‐J2 fibroblasts induce high levels of functions in PHHs, which is likely due to the ability of the 3T3‐J2 fibroblasts to express diverse hepatocyte‐supportive molecules present in the liver, such as decorin and T‐cadherin . Furthermore, the use of 3T3‐J2 fibroblasts in co‐culture with PHHs does not prevent the effective use of the stabilized PHHs for many applications in drug development (drug toxicity assessment, and hepatitis B/C viral infections) . Therefore, here we created co‐cultures of PHHs and 3T3‐J2 fibroblasts on heparin‐terminated and fibronectin‐coated PEMs and compared the long‐term morphology and functions to those obtained on fibronectin‐coated TCPS (conventional methodology).…”

Section: Discussionmentioning

confidence: 99%

A polyelectrolyte multilayer platform for investigating growth factor delivery modes in human liver cultures

Lin

Romero

Sorokina

et al. 2017

J Biomedical Materials Res

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Polyelectrolyte multilayers (PEMs) of chitosan and heparin are useful for mimicking growth factor (GF) binding to extracellular matrix (ECM) as in vivo. Here, we developed a PEM platform for delivering bound/adsorbed GFs to monocultures of primary human hepatocytes (PHHs) and PHH/non-parenchymal cell (NPC) co-cultures, which are useful for drug development and regenerative medicine. The effects of ECM protein coating (collagen I, fibronectin, and Matrigel®) and terminal PEM layer on PHH attachment/functions were determined. Then, heparin-terminated/fibronectin-coated PEMs were used to deliver varying concentrations of an adsorbed model GF, transforming growth factor β (TGFβ), to PHH monocultures while using soluble TGFβ delivery via culture medium as the conventional control. Soluble TGFβ delivery caused a severe, monotonic, and sustained downregulation of all PHH functions measured (albumin and urea secretions, cytochrome-P450 2A6 and 3A4 enzyme activities), whereas adsorbed TGFβ delivery caused transient upregulation of 3 out of 4 functions. Finally, functionally stable co-cultures of PHHs and 3T3-J2 murine embryonic fibroblasts were created on the heparin-terminated/fibronectin-coated PEMs modified with adsorbed TGFβ to elucidate similarities and differences in functional response relative to the monocultures. In conclusion, chitosan-heparin PEMs constitute a robust platform for investigating the effects of GF delivery modes on PHH monocultures and PHH/NPC co-cultures. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 971-984, 2018.

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Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Cited by 72 publications

References 54 publications

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

A polyelectrolyte multilayer platform for investigating growth factor delivery modes in human liver cultures

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