Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver

Hashimoto, Mari; Kobayashi, Kaoru; Watanabe, Mio; Kazuki, Yasuhiro; Takehara, Shoko; Inaba, Asumi; Nitta, Shin-Ichiro; Senda, Naoto; Oshimura, Mitsuo; Chiba, Kazuhiro

doi:10.1194/jlr.m033464

Cited by 29 publications

(18 citation statements)

References 52 publications

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“…Furthermore, cumulative evidence in the literature points to a functional role of the peroxisome in cholesterol metabolism, which is consistent with the fact that part of the isoprenoid pathway is localized within the peroxisomal matrix [11,25,33,[45][46][47][48][49]. Therefore, to further establish without any ambiguity that ThB plays a functional in cholesterol homeostasis in mice, we evaluated plasma lathosterol to cholesterol ratio, a parameter that often serves as a surrogate marker for global cholesterol synthesis, because it correlates well with the cholesterol balance [50][51][52]. Unlike cholesterol, the pool of lathosterol is small and turns over rapidly, making 2 lathosterol an analyte of choice [53].…”

Section: Whole Body Cholesterol De Novo Biosynthesis Is Increased In mentioning

confidence: 70%

Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents

Nicolas-Francès¹,

Arnauld²,

Kaminski³

et al. 2014

Biochimie

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The peroxisomal 3-ketoacyl-CoA thiolase B (ThB) catalyzes the thiolytic cleavage of straight chain 3-ketoacyl-CoAs. Up to now, the ability of ThB to interfere with lipid metabolism was studied in mice fed a laboratory chow enriched or not with the synthetic agonist Wy14,643, a pharmacological activator of the nuclear hormone receptor PPARα. The aim of the present study was therefore to determine whether ThB could play a role in obesity and lipid metabolism when mice are chronically fed a synthetic High Fat Diet (HFD) or a Low Fat Diet (LFD) as a control diet. To investigate this possibility, wild-type (WT) mice and mice deficient for Thb (Thb(-/-)) were subjected to either a synthetic LFD or a HFD for 25 weeks, and their responses were compared. First, when fed a normal regulatory laboratory chow, Thb(-/-) mice displayed growth retardation as well as a severe reduction in the plasma level of Growth Hormone (GH) and Insulin Growth Factor-I (IGF-I), suggesting alterations in the GH/IGF-1 pathway. When fed the synthetic diets, the corrected energy intake to body mass was significantly higher in Thb(-/-) mice, yet those mice were protected from HFD-induced adiposity. Importantly, Thb(-/-) mice also suffered from hypoglycemia, exhibited reduction in liver glycogen stores and circulating insulin levels under the LFD and the HFD. Thb deficiency was also associated with higher levels of plasma HDL (High Density Lipoproteins) cholesterol and increased liver content of cholesterol under both the LFD and the HFD. As shown by the plasma lathosterol to cholesterol ratio, a surrogate marker for cholesterol biosynthesis, whole body cholesterol de novo synthesis was increased in Thb(-/-) mice. By comparing liver RNA from WT mice and Thb(-/-) mice using oligonucleotide microarray and RT-qPCR, a coordinated decrease in the expression of critical cholesterol synthesizing genes and an increased expression of genes involved in bile acid synthesis (Cyp7a1, Cyp17a1, Akr1d1) were observed in Thb(-/-) mice. In parallel, the elevation of the lathosterol to cholesterol ratio as well as the increased expression of cholesterol synthesizing genes were observed in the kidney of Thb(-/-) mice fed the LFD and the HFD. Overall, the data indicate that ThB is not fully interchangeable with the thiolase A isoform. The present study also reveals that modulating the expression of the peroxisomal ThB enzyme can largely reverberate not only throughout fatty acid metabolism but also cholesterol, bile acid and glucose metabolism.

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Section: Whole Body Cholesterol De Novo Biosynthesis Is Increased In mentioning

confidence: 70%

Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents

Nicolas-Francès¹,

Arnauld²,

Kaminski³

et al. 2014

Biochimie

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“…CAR and PXR crosstalk and there is weak but insignificant induction of several other CAR/PXR regulated CYPs [4, 16, 74] including Cyp2b10, Cyp2c29, and Cyp2c40 (Table 2) with increased protein levels of CYP2B (Fig 4 ) . Therefore, we consider it more likely that PXR activity is increased potentially due to a lack of metabolism of a CYP3A metabolized endobiotic such as bile acids that in turn activate PXR [19, 75, 76]. …”

Section: Resultsmentioning

confidence: 99%

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

et al. 2017

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Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

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“…11 With the exception of drug metabolism impairment, no other major phenotype could be detected in Cyp3a knockout mice. 21,22 Alternative enzymes may have compensated the effect on the metabolism of endogenous compounds, whereas the prominent decrease in xenobiotic biotransformation would only manifest after xenobiotic exposure. In contrast, in a human CYP3A4-transgenic mouse line, the females were found to be deficient in lactation, leading to a markedly lower pup survival, and the mammary glands of the Tg-CYP3A4 lactating mothers had underdeveloped alveoli with low milk content.…”

Section: Discussionmentioning

confidence: 97%

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme

et al. 2014

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Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

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Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver

Cited by 29 publications

References 52 publications

Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents

Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme

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