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Consumption of a Western diet is an important risk factor for several chronic diseases including nonalcoholic fatty liver disease (NAFLD), but its effect on the xenobiotic metabolizing enzyme activities in the liver has been studied incompletely. In this study, male LDLr−/−ApoB100/100 mice were fed with Western diet (WD) or a standard diet for five months to reveal the effects on drug metabolism such as cytochrome P450 (CYP) oxidation and conjugation activities in the liver. Hepatic steatosis, lobular inflammation, and early fibrosis were observed in WD fed mice, but not in chow diet control mice. When compared to the controls, the WD-fed mice had significantly decreased protein-normalized CYP probe activities of 7-ethoxyresorufinO-deethylation (52%), coumarin 7-hydroxylation (26%), 7-hydroxylation of 3-(3-fluoro-4-hydroxyphenyl)-6-methoxycoumarin (70%), 7-hydroxylation of 3-(4-trifluoromethoxyphenyl)-6-methoxycoumarin (78%), 7-hydroxylation of 3-(3-methoxyphenyl)coumarin (81%), and pentoxyresorufin O-depentylation (66%). Increased activity was seen significantly in sulfonation of 3-(4-methylphenyl)-7-hydroxycoumarin (289%) and cytosol catechol O-methyltranferase (COMT, 148%) in the WD group when compared to the controls. In conclusion, the WD-induced steatosis in male LDLr−/−ApoB100/100 mice was associated with decreased CYP oxidation reactions but had no clear effects on conjugation reactions of glucuronidation, sulfonation, and cytosolic catechol O-methylation. Consequently, the WD may decrease the metabolic elimination of drugs compared to healthier low-fat diets. [ABSTRACT FROM AUTHOR]

Aims Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR−/−), and LDLR−/− mice expressing apoB-100 only (LDLR−/− ApoB100/100) having a humanized lipoprotein profile. Methods and results LDLR−/− mice were fed a high-fat diet (HFD) for 6 or 12 weeks and LDLR−/−ApoB100/100 mice a regular chow diet for 6 or 12 months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR−/− mice reduced total plasma cholesterol after 6 weeks of HFD and triglycerides in LDLR−/−ApoB100/100 mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR−/−ApoB100/100 mice as it increased plaque calcification. Moreover, ∼36% of Nrf2−/−LDLR−/−ApoB100/100 females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12 months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR−/−ApoB100/100 female mice at age of 12 months. Conclusions Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR−/−ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death. [ABSTRACT FROM AUTHOR]

Background: In aortic stenosis (AS), valvular calcification makes valves thicker and stiff causing impairment of the valve function. The aortic valves do not open properly and most of the AS patients have also difficulties in the closing of aortic valves. We used high-resolution cine- magnetic resonance imaging (MRI) to study changes in the mobility of the aortic valves in LDLr-/-ApoB100/100 mice, the model of AS. In addition, morphology of the aortic valves and left ventricular function were determined. Methods: LDLr-/-ApoB100/100 mice were fed a western diet (WD) (42 % kcal from fat) or a normal chow diet (control) for 5 months. The mice were imaged at 7T Bruker Pharmascan using volume transmitter and surface receiver coil. Aortic valve function was examined by imaging the cross section of the aorta at valve level using cine sequence; parameters were; slice thickness 0.6 mm, TR = 8 ms, TE = 2 ms, FOV = 1,5 x 3 cm2, matrix size 192 x 192, 1 slice, and 3 averages. From these images, the area of aortic valve orifice was determined during heart cycle. Heart function was studied from 6-8 cine-images covering the whole heart from apex to aorta; parameters for imaging: TR =8 ms, TE = 2 ms, FOV = 4 x 4 cm2, matrix size 192 x 192, 1 slice, slice thickness 1 mm, 10-14 frames depending on heart rate, and 2 averages. Hematoxylin-eosin staining of aortic valves was conducted. Results: The opening and closing of the aortic valves were evaluated and the data indicated clear functional impairment of aortic valves in WD mice when compared to control mice (interaction P=0.0004), figure 1. MRI showed narrowing (14%, p<0.05) of the orifice area, and this was seen also in histology (34%, p<0.05) indicating more severe AS after WD when compared to controls. Additionally, MRI revealed reduction in EF in mice fed with WD compared to controls (11%, p<0.01). Conclusion: Cine-MRI can be used to detect aortic valve dysfunctionality. In addition, these findings support the use of hypercholesterolemic mice on WD as a model of AS. [ABSTRACT FROM AUTHOR]

Consumption of a Western diet is an important risk factor for several chronic diseases including nonalcoholic fatty liver disease (NAFLD), but its effect on the xenobiotic metabolizing enzyme activities in the liver has been studied incompletely. In this study, male LDLr -/- ApoB 100/100 mice were fed with Western diet (WD) or a standard diet for five months to reveal the effects on drug metabolism such as cytochrome P450 (CYP) oxidation and conjugation activities in the liver. Hepatic steatosis, lobular inflammation, and early fibrosis were observed in WD fed mice, but not in chow diet control mice. When compared to the controls, the WD-fed mice had significantly decreased protein-normalized CYP probe activities of 7-ethoxyresorufinO-deethylation (52%), coumarin 7-hydroxylation (26%), 7-hydroxylation of 3-(3-fluoro-4-hydroxyphenyl)-6-methoxycoumarin (70%), 7-hydroxylation of 3-(4-trifluoromethoxyphenyl)-6-methoxycoumarin (78%), 7-hydroxylation of 3-(3-methoxyphenyl)coumarin (81%), and pentoxyresorufin O-depentylation (66%). Increased activity was seen significantly in sulfonation of 3-(4-methylphenyl)-7-hydroxycoumarin (289%) and cytosol catechol O-methyltranferase (COMT, 148%) in the WD group when compared to the controls. In conclusion, the WD-induced steatosis in male LDLr -/- ApoB 100/100 mice was associated with decreased CYP oxidation reactions but had no clear effects on conjugation reactions of glucuronidation, sulfonation, and cytosolic catechol O-methylation. Consequently, the WD may decrease the metabolic elimination of drugs compared to healthier low-fat diets., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Markus Koponen et al.)