Unavailability of liver triacylglycerol increases serum cholesterol concentration induced by dietary cholesterol in exogenously hypercholesterolemic (ExHC) rats

Tanaka, Yasutake; Nagao, Koji; Nakagiri, Hideaki; Nagaso, Toshirou; Iwasa, Yasue; Mori, Hikari; Amaki, Makoto; Imaizumi, Kazunori; Sato, Masao

doi:10.1186/1476-511x-13-19

Cited by 4 publications

(16 citation statements)

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“…In our previous studies, we identified Smek2 as one of the genes responsible for DIHC in ExHC rats [15], and we revealed that Smek2 dysfunction causes impairment of de novo fatty acid synthesis in the liver of ExHC rats to develop DIHC via β-migration of secreted VLDL [15,16]. High sucrose diet is known to activate hepatic fatty acid synthesis [25].…”

Section: Plos Onementioning

confidence: 98%

“…In this study, we conducted two experiments with three types of diet, different ratios of carbohydrates (glucose, sucrose, and fructose). As we reported, ExHC rats show low FAS activities even though being fed the high-sucrose diet [16]. Therefore, we conducted the experiment 1 with a hypothesis that ExHC rats had an impaired metabolism of fructose, which can skip the rate-limiting reaction of glycolysis and be more rapidly metabolized than glucose.…”

Section: Introductionmentioning

confidence: 99%

“…To reveal the mechanism underlying the development of DIHC, we performed comparative studies with ExHC, SD, and ExHC.BN-Dhic2 BN congenic rats (described as Congenic rats in the following text), which have the Dich2 locus derived from Brown-Norway (BN) rats, used as a genetic standard strain, and genetic background of ExHC rats [15]. Under the sucrose-diet-fed condition activating hepatic de novo fatty acid synthesis, the ExHC rats showed low hepatic fatty acid synthase (FAS) activity and low hepatic triacylglycerol (TAG) levels because of Smek2 dysfunction [16]. The shortage of hepatic TAG resulted in the retention of very low-density lipoprotein (VLDL) via β-migration (increase in cholesterol-ester population in secreted VLDL) [16].…”

Section: Introductionmentioning

confidence: 99%

“…Under the sucrose-diet-fed condition activating hepatic de novo fatty acid synthesis, the ExHC rats showed low hepatic fatty acid synthase (FAS) activity and low hepatic triacylglycerol (TAG) levels because of Smek2 dysfunction [16]. The shortage of hepatic TAG resulted in the retention of very low-density lipoprotein (VLDL) via β-migration (increase in cholesterol-ester population in secreted VLDL) [16]. However, the mechanism underlying the depression of hepatic FAS activity caused by Smek2 dysfunction is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the highsucrose-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 highsucrose 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-Dihc2 BN , 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.

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Section: Plos Onementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…It is well documented that rats [7], mice [8], rabbits [9], guinea pig [10], hamster [11], and gerbil [12] are used for modeling human HLP. Among them, rats, hamster and mice are the most extensively used animals [13][14][15][16][17][18][19]. However, the molecular basis of pathogenesis in hyperlipidemic rats, hamster and mice model induced by HFD remain unclear, which limits its predictability and accuracy on evaluating lipid-lowering agents for human HLP.…”

Section: Introductionmentioning

confidence: 99%

Impaired reverse cholesterol transport and hepatic steatosis contribute to pathogenesis of high fat dietinduced hyperlipidemia in murine models

Zeng¹,

Sun²,

Yao³

et al. 2016

Trop. J. Pharm Res

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α‐globulin‐rich rice cultivar, low glutelin content‐1 (LGC‐1), decreases serum cholesterol concentration in exogenously hypercholesterolemic rats

et al. 2021

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BACKGROUND: Rice ⊍-globulin has been reported to have serum cholesterol-lowering activity in rats. However, it is still unclear whether ⊍-globulin exerts this effect when taken as one of the dietary components. In the present study, we investigated the effect of two cultivars of rice, low glutelin content (LGC)-1 and LGC-Jun, on reducing serum cholesterol in exogenously hypercholesterolemic (ExHC) rats. LGC-1 is enriched in ⊍-globulin (10.6 mg g −1 rice flour, which is an approximately 1.5 times higher ⊍-globulin content than in Koshihikari a predominant rice cultivar in Japan), whereas LGC-Jun is a globulin-negative cultivar. METHODS: ExHC rats, the model strain of diet-induced hypercholesterolemia, were fed 50% LGC-1 or LGC-Jun and 0.5% cholesterol-containing diets for 2 weeks, followed by measurement of cholesterol metabolism parameters in serum and tissues. RESULTS: Serum cholesterol and non-high-density lipoprotein cholesterol levels were significantly lower in the LGC-1 group compared to the LGC-Jun group. Cholesterol intestinal absorption markers, hepatic and serum levels of campesterol and ⊎-sitosterol, and lymphatic cholesterol transport were not different between the two groups. Levels of 7⊍-hydroxycholesterol, an intermediate of bile acid synthesis, showed a downward trend in the livers of rats that were fed LGC-1 (P = 0.098). There was a significant decrease in the hepatic mRNA expression of Cyp7a1 (a synthetic enzyme for 7⊍-hydroxycholesterol) in the LGC-1 group compared to the LGC-Jun group. CONCLUSION: DietaryLGC-1 significantly decreased serum cholesterol levels in ExHC rats. The possible mechanism for the cholesterol-lowering activity of LGC-1 is partial inhibition of bile acid and cholesterol synthesis in the liver.

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Unavailability of liver triacylglycerol increases serum cholesterol concentration induced by dietary cholesterol in exogenously hypercholesterolemic (ExHC) rats

Cited by 4 publications

References 41 publications

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

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

Impaired reverse cholesterol transport and hepatic steatosis contribute to pathogenesis of high fat dietinduced hyperlipidemia in murine models

α‐globulin‐rich rice cultivar, low glutelin content‐1 (LGC‐1), decreases serum cholesterol concentration in exogenously hypercholesterolemic rats

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