Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

Ghoneim, Ragia H.; Sock, Émilienne T. Ngo; Lavoie, Jean‐Marc; Piquette-Miller, Micheline

doi:10.1017/s0007114514003717

Cited by 37 publications

(27 citation statements)

References 54 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the context of previous reports, results in mouse models of NAFLD have been heterogeneous with some demonstrating decreased (Yoshinari et al, 2006;Ghose et al, 2011;Wahlang et al, 2014) or induced (Fisher et al, 2008;Spruiell et al, 2014) expression of Cyp3a11. Similarly, rat models of hepatic steatosis are conflicting, with some reporting decreased Cyp3a expression (Leclercq et al, 1998) and others showing higher levels (Ghoneim et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Woolsey¹,

Mansell²,

Kim³

et al. 2015

Drug Metab Dispos

109

113

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4b-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4b-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4b-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipidloaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Woolsey¹,

Mansell²,

Kim³

et al. 2015

Drug Metab Dispos

109

113

View full text Add to dashboard Cite

show abstract

“…Second, Kim et al also showed for comparison, that along with FXR, PXR acetylation levels are also elevated in response to HFD-induced obesity in mouse liver, suggesting that obesity may represent the physiological relevance of PXR acetylation. In this context, HFD in rodents also increases PXR levels, perhaps highlighting the significance for overall PXR acetylation effects in obesity [86]. In fact, it is becoming clear that nutrient excess conditions promote global hepatic acetylation of metabolic regulators in general, including NRs, for metabolic adaptation [87–93].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it is becoming clear that nutrient excess conditions promote global hepatic acetylation of metabolic regulators in general, including NRs, for metabolic adaptation [87–93]. A counter argument is that this acetylation state/level could simply reflect an adaptation to increased expression of PXR in HFD- fed rodents [86, 94, 95]. …”

Section: Discussionmentioning

confidence: 99%

“…SIRT1 mediated deacetylation of PXR could be particularly relevant with environmental contaminants that could enhance fatty liver formation via PXR and other related nuclear receptors [112]. Likewise, dietary changes (e.g., fat feeding) could alter PXR levels as well as influence its acetylation [82, 113], so in these conditions the relative activation of SIRT1 becomes critical in determining the overall effects of PXR in metabolic syndromes. We have shown that SIRT1 is partially responsible for the deacetylation of PXR.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Pasquel¹,

Doricakova²,

Li³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

View full text Add to dashboard Cite

Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug–drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC–MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels.

show abstract

“…In LPM from HFD-fed mice, no significant change in ABCA1 expression was observed, despite the increased ubiquitination of ABCA1. This is likely to be because of the net outcome of transcriptional induction of ABCA1 mRNA 30,31 and lysosomal degradation of ubiquitinated csABCA1.…”

Section: Decreased Interaction Of Abca1 With Lxrβ and Increased Ubiqumentioning

confidence: 99%

Cellular Cholesterol Accumulation Facilitates Ubiquitination and Lysosomal Degradation of Cell Surface–Resident ABCA1

Mizuno

Hayashi

Kusuhara

2015

ATVB

View full text Add to dashboard Cite

Objective-By excreting cellular cholesterol to apolipoprotein A-I, ATP-binding cassette transporter A1 (ABCA1) mediates the biogenesis of high-density lipoprotein in hepatocytes and prevents foam cell formation from macrophages. We recently showed that cell surface-resident ABCA1 (csABCA1) undergoes ubiquitination and later lysosomal degradation through the endosomal sorting complex required for transport system. Herein, we investigated the relevance of this degradation pathway to the turnover of csABCA1 in hypercholesterolemia. Approach and Results-Immunoprecipitation and cell surface-biotinylation studies with HepG2 cells and mouse peritoneal macrophages showed that the ubiquitination level and degradation of csABCA1 were facilitated by treatment with a liver X receptor (LXR) agonist and acetylated low-density lipoprotein. The effects of an LXR agonist and acetylated lowdensity lipoprotein on the degradation of csABCA1 were repressed completely by treatment with bafilomycin, an inhibitor of lysosomal degradation, and by depletion of tumor susceptibility gene 101, a major component of endosomal sorting complex required for transport-I. RNAi analysis indicated that LXRβ inhibited the accelerated lysosomal degradation of csABCA1 by the LXR agonist, regardless of its transcriptional activity. Cell surface coimmunoprecipitation with COS1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that LXRβ interacted with csABCA1 and inhibited the ubiquitination of csABCA1. Immunoprecipitates with anti-ABCA1 antibodies from the liver plasma membranes showed less LXRβ and a higher ubiquitination level of ABCA1 in high-fat diet-fed mice than in normal chow-fed mice. (csABCA1) is considered to be important to understanding the regulation of ABCA1 function. A key molecule for the degradation of csABCA1 is the protease calpain, which can cleave ABCA1 in the intracellular compartment or at the cell surface. Conclusions-Under15,16 However, calpain seems not to be involved in the accelerated degradation of ABCA1 induced by loading with free cholesterol and unsaturated fatty acids. 10,11 We recently found another degradation mechanism of csABCA1 that is independent of the calpain protease-involving machinery. Through this mechanism, ubiquitination, a regulated posttranslational modification that conjugates ubiquitin to lysine residues of targeted proteins, acts as a signal for the degradation of csABCA1 by the direction of ubiquitinated csABCA1 to lysosomal degradation. 17This degradation process involves the endosomal sorting complex required for transport (ESCRT) system, a set of proteins comprising ESCRT-0, -I, -II, and -III, which recognizes ubiquitinated cargo in the early endosome and mediates its recruitment to and incorporation into multivesicular bodies, leading to lysosomal degradation. [18][19][20] To explore the possibility of restoring the turnover of csABCA1 and inhibiting progression of atherosclerosis in hypercholesterolemia, in the current study, we focused on the ubiquitination-mediated lysosomal de...

show abstract

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

Cited by 37 publications

References 54 publications

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Cellular Cholesterol Accumulation Facilitates Ubiquitination and Lysosomal Degradation of Cell Surface–Resident ABCA1

Contact Info

Product

Resources

About