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. 2020 Jan;10(1):171-185.
doi: 10.1016/j.apsb.2019.10.009. Epub 2019 Nov 28.

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice

Pei Wang  1   2 , Xueyan Shao  2 , Yifan Bao  2 , Junjie Zhu  3 , Liming Chen  2 , Lirong Zhang  1 , Xiaochao Ma  3 , Xiao-Bo Zhong  2
Affiliations

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice

Pei Wang et al. Acta Pharm Sin B. 2020 Jan.

Abstract

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for Cyp2c29 and 3a11) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.

Keywords: 18-HA, adult mice fed with 18 weeks HFD; 18-LA, adult mice fed with 18 weeks LFD; 4-HA, adult mice fed with 4 weeks HFD; 4-LA, adult mice fed with 4 weeks LFD; 7-ER, 7-ethoxyresorufin; 8-HA, adult mice fed with 8 weeks HFD; 8-LA, adult mice fed with 8 weeks LFD; AhR, aryl hydrocarbon receptor; BMI, body mass index; CAR, constitutive androstane receptor; CHZ, chlorzoxazone; CYP2E1, cytochrome P450 2E1; DIO, diet-induced obesity; DMEs, drug-metabolizing enzymes; Diet-induced obesity; Drug-metabolizing enzymes; EFV, efavirenz; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; HFD, high-fat diet; HNF4α, hepatocyte nuclear factor 4 alpha; High-fat diet; LFD, low-fat diet; MDZ, midazolam; MPA, mobile phase A; MPB, mobile phase B; NADPH, nicotinamide adenine dinucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; NRs, nuclear receptors; Nuclear receptors; O-18-HA, offspring from parental mice fed with 18 weeks HFD; O-18-LA, offspring from parental mice fed with 18 weeks LFD; O-4-HA, offspring from parental mice fed with 4 weeks HFD; O-4-LA, offspring from parental mice fed with 4 weeks LFD; O-8-HA, offspring from parental mice fed with 8 weeks HFD; O-8-LA, offspring from parental mice fed with 8 weeks LFD; Ontogenic expression; Overweight; PBS, phosphate-buffered saline; PPARα, peroxisome proliferator-activated receptor alpha; PXR, pregnane X receptor; RSF, resorufin; RT-qPCR, real-time quantitative PCR; SD, standard deviation; SULT1A1, sulfotransferase 1A1; UGT1A1, uridine diphosphate glucuronosyltransferase 1A1.

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Figures

Image 1
Graphical abstract
Figure 1
Figure 1
Impacts of HFD-feeding durations on the body weight gain, liver weight, and liver appearance of adult mice. (A) A schematic study design. Male and female mice (4–5 weeks old) were fed with either a LFD or HFD for 4, 8, or 18 weeks (n = 3–7 per group). Body weight gain (B) and liver weight (C) of both male and female adult mice after different feeding durations under a LFD or HFD were measured. (D) Representative liver images from each group. Data are depicted as mean ± SD. Each dot represents a value from one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the corresponding LFD groups.
Figure 2
Figure 2
Effects of HFD-feeding durations on the hepatic expression of NRs and DMEs in adult mice. Male and female mice (4–5 weeks old) were fed with either a LFD or HFD for 4, 8, or 18 weeks (n = 3–7 per group). At the end of each period, liver tissues were collected to determine the mRNA expression levels of NRs and DMEs and the enzyme activities of selected DMEs. (A)–(K) The mRNA expression levels were determined using the RT-qPCR method and normalized to Gapdh. The relative mRNA expression levels were calculated using the 2−ΔΔCt method compared to the LFD groups. (L) Enzyme activities of CYP1A, 2B, 2E, and 3A in four random selected male adult mice after 8 weeks with a LFD or HFD were determined by the UPLC-QTOFMS method and expressed as the formation rates of RSF, 8-OH-EFV, 6-OH-CHZ, and 1-OH-MDZ, respectively. Data are depicted as mean ± SD. Each dot represents a value from one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the corresponding LFD groups.
Figure 3
Figure 3
Impacts of parental HFD on the body weight and liver weight of offspring. (A) A schematic study design. After being fed with either a LFD or HFD for 8 weeks at an age of 4–5 weeks, mice were mated. The offspring were sacrificed at different ages after birth (n = 3–6 per group). Body weight (B) and liver weight (C) of offspring were measured. Data are depicted as mean ± SD. Each dot represents a value from one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
Figure 4
Figure 4
Effects of parental HFD on the hepatic expression of NRs in offspring. The offspring derived from parental mice fed with a LFD or HFD for 8 weeks were sacrificed at different ages after birth (n = 3–6 per group). The liver tissues were collected to determine the mRNA expression levels of NRs. The mRNA expression levels were measured using the RT-qPCR method and calculated using the 2−ΔΔCt method with normalizations to Gapdh. Data are depicted as mean ± SD. Each dot represents a fold change in gene expression of one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
Figure 5
Figure 5
Effects of parental HFD on the ontogenic expression patterns of DMEs in offspring liver. The offspring derived from parental mice fed with a LFD or HFD for 8 weeks were sacrificed at different ages after birth (n = 3–6 per group). The liver tissues were collected to determine the mRNA expression levels and enzyme activities of DMEs. (A)–(F) The mRNA expression levels were measured using the RT-qPCR method and normalized to Gapdh. The upper panels (relative mRNA expression levels) were calculated using the 2−ΔΔCt method compared to the LFD groups. The lower panels (mRNA expression levels) were expressed as 2–[Ct(DMEs) − Ct(Gadph)]. (G) Enzyme activities of CYP1A, 2B, 2E, and 3A in four random selected male offspring at day 30 from the LFD or HFD group were determined by the UPLC–QTOFMS method and expressed as the formation rates of RSF, 8-OH-EFV, 6-OH-CHZ, and 1-OH-MDZ, respectively. Data are depicted as mean ± SD. Each dot represents a value from one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
Figure 6
Figure 6
Impacts of HFD-feeding durations of parental mice on the body weight and liver weight of offspring. (A) A schematic study design. After being fed with either a LFD or HFD for 4 or 18 weeks at an age of 4–5 weeks, mice were mated. The offspring were sacrificed at different ages after birth (n = 3–6 per group). Body weight and liver weight of offspring were measured. (B) Body weight and liver weight of male and female offspring (postnatal days 15, 20, 30, or 60) derived from parental mice fed with a LFD or HFD for 4 weeks. (C) Body weight and liver weight of male offspring (postnatal day 60) derived from parental mice fed with a LFD or HFD for 18 weeks. Data are depicted as mean ± SD. Each dot represents a value from one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
Figure 7
Figure 7
Effects of HFD-feeding durations of parental mice on the hepatic expression of NRs in offspring. After being fed with either a LFD or HFD for 4 or 18 weeks, mice were mated. The offspring were sacrificed at different ages after birth (n = 3–6 per group). The liver tissues were collected to determine the mRNA expression levels of NRs. (A)–(E) The mRNA expression of NRs in the liver of offspring derived from LFD- or HFD-fed parental mice for 4 weeks. (F) The mRNA expression levels of NRs in the liver of offspring derived from LFD- or HFD-fed parental mice for 18 weeks. The mRNA expression levels were measured using the RT-qPCR method and calculated using the 2−ΔΔCt method with normalizations to Gapdh. Data are depicted as mean ± SD. Each dot represents a fold change in gene expression of one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
Figure 8
Figure 8
Effects of HFD-feeding durations of parental mice on the hepatic expression levels of DMEs in offspring. (A)–(H) The mRNA expression levels of DMEs in the liver of offspring derived from LFD- or HFD-fed parental mice for 4 weeks (n = 5–6 per group). The mRNA expression levels were determined using the RT-qPCR method and calculated using the 2–ΔΔCt method with normalizations to Gapdh. Data are depicted as mean ± SD. Each dot represents a fold change in gene expression of one mouse. Statistical significance between two groups was determined by an unpaired Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, HFD versus the age-matched LFD groups.
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References

    1. World Health Organization. reportObesity: preventing and managing the global epidemic. Report of a WHO consultation (WHO Technical Report Series 894). Available from: https://www.who.int/nutrition/publications/obesity/WHO_TRS_894/en/. - PubMed
    1. NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017;390:2627–2642. - PMC - PubMed
    1. Liu J.X., Wang Y.T., Lin L.G. Small molecules for fat combustion: targeting obesity. Acta Pharm Sin B. 2019;9:220–236. - PMC - PubMed
    1. World Health Organization. Fact sheets: obesity and overweight. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
    1. Zhang Y.X., Wang Z.X., Zhao J.S., Chu Z.H. The current prevalence and regional disparities in general and central obesity among children and adolescents in Shandong, China. Int J Cardiol. 2017;227:89–93. - PubMed