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High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

ABSTRACT: Background:Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. Methods:Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35?days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100?mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. Results:The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. Conclusion:Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6945706 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

Kumar Avinash A Pathak Rashmi R Palfrey Henry A HA Stone Kirsten P KP Gettys Thomas W TW Murthy Subramanyam N SN

Nutrition & metabolism 20200106

<h4>Background</h4>Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin wou ...[more]

PMID: 31921324

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Project description:This study examined the influence of a diet enriched with free methionine (dl-Met) or methionine dipeptide (dl-MMet) on the intestinal health of Eimeria-challenged (EC) and unchallenged (UC) broilers. A non-supplemented, methionine-deficient diet (NS) was used as control. Treatments were arranged in a 2 × 3 factorial completely randomized design with eight replications. Broilers in the EC group were infected with sporulated oocysts of Eimeria spp. (E. acervulina, E. maxima, E. praecox, and E. mitis) at 14 d of age. Performance analysis, light and electron microscopy of the jejunum, analysis of genes related to apoptosis and cell proliferation in the jejunum, and blood tests were performed at 6 days post-inoculation (dpi). EC broilers had poorer performance than UC broilers, regardless of diet (P < 0.001). Broilers fed the dl-Met diet had greater weight gain (P = 0.004) and lower feed conversion ratio (P = 0.019) than broilers fed other diets. Jejunal sections from EC broilers fed the NS diet showed short (P = 0.001) and wide villi (P < 0.001) with increased crypt depth (P < 0.001) and reduced villus / crypt ratio (P = 0.001), jejunal absorptive surface area (P < 0.001), number of neutral goblet cells (Eimeria challenge: P = 0.048; diet P = 0.016), and mucin 2 (MUC2) gene expression (P = 0.018). EC birds fed the dl-MMet diet had higher enterocyte height (P < 0.001). Birds fed the dl-MMet diet had low lamina propria width (P = 0.009). UC broilers fed the dl-Met diet had the highest number of acidic goblet cells (P = 0.005), whereas EC broilers assigned the dl-MMet diet showed the highest number of intraepithelial lymphocytes (P = 0.033). Reduced expression of caspase-3 (CASP3) (P = 0.005), B-cell lymphoma 2 (BCL2) (P < 0.001), mechanistic target of rapamycin (MTOR) (P < 0.001), and ribosomal protein S6 kinase B1 (RPS6KB1) (P < 0.001) genes was observed in EC animals. MTOR expression levels were highest in birds fed the dl-MMet diet (P = 0.004). Plasma activities of aspartate aminotransferase (AST) was influenced by both diet (P = 0.002) and Eimeria challenge (P = 0.005), with EC broilers assigned the NS diet showing the highest levels. EC broilers fed the NS diet had higher creatine kinase (CK) activity (P = 0.049). EC broilers had lower plasma uric acid (P = 0.004) and higher serum mucoproteins level (P < 0.001). These results indicate that methionine dipeptide supplementation is able to mitigate the harmful intestinal effects of Eimeria spp. in broilers.

Project description:The effects that maternal dietary methionine have on progeny have been reported on broilers. However, the paternal effects are not known, so the current study was conducted to explore the influences of paternal dietary methionine (Met) have on progeny carcass traits, meat quality, and related gene expressions. A total of 192 hens and 24 roosters from Ross parent stock at 36 weeks of age were selected. From week 37 to 46, the roosters were allocated to two groups with three replicates of 4 cocks each, (control, 0.28% Met), and methionine group (MET group, 0.28% Met + 0.1% coated Met). The results revealed that, although the heavier live body weight in progeny at day 49 of control group compared to MET group (p < 0.05), the relative eviscerated yield and relative thigh muscle yield were higher in MET group (p < 0.05); but the relative abdominal fat was lower (p < 0.05). In thigh and breast muscles, a positive response of pH24 h value, shear force (g) and drip loss (%) were observed in MET group (p < 0.05). The lightness (L) and redness (a) were increased (p < 0.05) in breast muscles of MET group, while only the redness (a*24 h) and yellowness (b*24 h) were increased (p < 0.05) in thigh muscles of MET group. The gender has a significant (p < 0.05) effect on carcass traits and muscle redness (a*), where these traits improved in males, and no interaction between treatments and gender were observed for these results. The expression levels of PRKAG2 and PRDX4 supported the changes in muscle pH, with these up-regulated in thigh and breast muscles of MET group, the PPP1R3A gene supported the changes in pH value being down-regulated (p < 0.01) in these same muscles. The BCO1 gene expression was consistent with the changes in meat color and was up-regulated (p < 0.01) in thigh muscles of MET group, consistent with the changes in b* color values. Finally, it was concluded that the supplementation of 0.1% Met to rooster diets could improve carcass characteristics and meat quality of progeny.

Dataset Information

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

Publications

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

Similar Datasets

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