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Low utilization of glucose in the liver causes diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats.

ABSTRACT: Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the high-sucrose-diet-feeding condition, a loss-of-function mutation in Smek2 results in low activity of fatty acid synthase (FAS) followed by the shortage of hepatic triacylglycerol content in ExHC rats and the onset of DIHC. However, the relationship between the Smek2 mutation and FAS dysfunction is still unclear. Here, we focused on carbohydrate metabolism, which provides substrates for FAS, and analyzed carbohydrate and lipid metabolisms in ExHC rats to clarify how the deficit of Smek2 causes DIHC. Male ExHC and SD rats were fed high-sucrose or high-starch diets containing 1% cholesterol for 2 weeks. Serum cholesterol levels of the ExHC rats were higher, regardless of the dietary carbohydrate. Hepatic triacylglycerol levels were higher in only the SD rats fed the high-sucrose diet. Moreover, the ExHC rats exhibited a diabetes-like status and accumulation of hepatic glycogen and low hepatic mRNA levels of liver-type phosphofructokinase (Pfkl), which encodes a rate-limiting enzyme for glycolysis. These results suggest that the glucose utilization, particularly glycolysis, is impaired in the liver of ExHC rats. To evaluate how the diet with extremely low glucose affect to DIHC, ExHC.BN-Dihc2BN, a congenic strain that does not develop DIHC, and ExHC rats were fed a high-fructose diet containing 1% cholesterol for 2 weeks. The serum cholesterol and hepatic triacylglycerol levels were similar in the strains. Results of water-soluble metabolite analysis with primary hepatocytes, an increase in fructose-6-phosphate and decreases in succinate, malate and aspartate in ExHC rats, support impaired glycolysis in the ExHC rats. Thus, the Smek2 mutation causes abnormal hepatic glucose utilization via downregulation of Pfkl expression. This abnormal glucose metabolism disrupts hepatic fatty acid synthesis and causes DIHC in the ExHC rats.

SUBMITTER: Tanaka Y

PROVIDER: S-EPMC7067558 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Low utilization of glucose in the liver causes diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats.

Tanaka Yasutake Y Ono Masahiro M Miyago Motonori M Suzuki Takahisa T Miyazaki Yurika Y Kawano Michio M Asahina Makoto M Shirouchi Bungo B Imaizumi Katsumi K Sato Masao M

PloS one 20200312 3

Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the high-sucrose-diet-feeding condition, a loss-of-function mutation in Smek2 results in low activity of fatty acid synthase (FAS) followed by the shortage of hepatic triacylglycerol content in ExHC rats and the onset of DIHC. However, the relationship between the Smek2 mutation and FAS dysfunction is still unclear. Here, we focused ...[more]

PMID: 32163433

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Project description:Sorghum bicolor grains are rich in phytochemicals known to considerably impact human health. Several health-promoting products such as flour, staple food, and beverages have been produced from sorghum grains. This study investigated the protective and modulatory effects of a sorghum diet on the genes of some antioxidant and glycolytic enzymes in alloxan-induced diabetic rats. The rats were randomly distributed into six groups: the control group received normal diet, while the other groups were pretreated with 12.5, 25, 50, 75, and 100% of the sorghum diets daily for 8 weeks before the administration of a dose of alloxan (100 mg/kg BW), after which blood was collected and the liver was excised. The effects of the diets on blood glucose levels, liver dysfunction indices, and markers of oxidative stress were assessed spectrophotometrically, while the gene expressions of key glycolytic enzymes and enzymatic antioxidants were assayed using reverse transcriptase polymerase chain reaction. It was observed that the pretreatment of the experimental animals with the diets normalized the blood glucose before and after the administration of alloxan. The sorghum-treated groups also showed statistically significant (p < 0.05) decrease in liver dysfunction indices and markers of oxidative damage compared with the control. In addition, statistically the diets significantly decreased (p < 0.05) the relative expression of superoxide dismutase, glutathione peroxidase, glucokinase, phosphofructokinase, and hexokinase genes in the experimental animals compared with the control. Overall, this study showed that the preadministration of fermented sorghum diet significantly protected against hyperglycemia and suppressed glucose utilization via glycolysis in the liver of alloxan-induced diabetic rats. Thus, the consumption of sorghum diet may protect against hyperglycemia and oxidative damage and may therefore serve as functional food for management of diabetic mellitus.

Dataset Information

Low utilization of glucose in the liver causes diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats.

Publications

Low utilization of glucose in the liver causes diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats.

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