Kumar Avinash, Pathak Rashmi, Palfrey Henry A, Stone Kirsten P, Gettys Thomas W, Murthy Subramanyam N
1Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA 70813 USA.
2Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA USA.
Nutr Metab (Lond). 2020 Jan 6;17:2. doi: 10.1186/s12986-019-0422-z. eCollection 2020.
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.
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.
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.
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.
胆固醇（Cho）和蛋氨酸（Met，同型半胱氨酸的前体）均为脂肪肝疾病的风险因素。由于西方饮食富含Cho和Met，我们研究了喂食富含Met和Cho的饮食对肝脏的影响。此外，基于已报道的西他列汀（一种抗糖尿病药物）的抗氧化和降脂特性，我们测试了其是否能够抵消高Cho和Met的负面影响。因此，我们假设西他列汀将改善因喂食富含Cho、Met或两者的饮食所导致的肝脏病理变化。
雄性斯普拉格-道利大鼠随意进食a）对照饮食，或b）高Met饮食，或c）高Cho饮食，或d）高Met + 高Cho饮食，持续35天。从第10天到第35天，每个饮食组中50%的大鼠通过灌胃给予溶媒或西他列汀水悬浮液（100 mg/kg/天）。采集肝脏样本进行组织学、分子和生化分析。
高Cho饮食导致显著的肝脏脂肪变性，西他列汀对此无影响。与预期相反，西他列汀加剧了喂食高Cho饮食大鼠肝脏氧化应激和纤维化标志物的表达。免疫组织化学和天狼星红染色显示4-羟基壬烯醛加合物和胶原沉积相应增加。高Met饮食的大鼠未出现这些肝脏变化，且与对照组相当。在高Cho饮食中添加Met可显著减轻单独高Cho饮食所导致的肝脏脂肪变性、氧化应激和纤维化。
西他列汀加剧了高Cho对氧化应激和纤维化的影响，导致出现类似非酒精性脂肪性肝炎的症状，而添加Met可显著逆转这些症状。
