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 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.

Mutation in Smek2 regulating hepatic glucose metabolism causes hypersarcosinemia and hyperhomocysteinemia in rats

“…The ExHC rats developed hypersarcosinemia and further homocysteinemia due to abnormal sarcosine metabolism caused by decreased Sardh expression. In addition to regulating glucose metabolism 4 , 5 , Smek2 is also important for regulating amino acid metabolism.…”

“…This deletion leads to disrupted SMEK2 protein function that is not fatal in rats. With respect to the pathological mechanism of DIHC in ExHC rats, we found that compared with the original Sprague–Dawley (SD) strain, ExHC rats have impaired liver glucose metabolism (low expression of liver-type phosphofructokinase, Pfkl , a rate-limiting enzyme of glycolysis) 4 , low de novo fatty acid synthesis in the liver due to a shortage of required precursors 5 , and that this shortage of fatty acids leads to hepatic secretion of β-VLDL that is slowly uptaken by the liver 5 . However, the mechanism of Pfkl downregulation by the loss-of-function of Smek2 is unclear.…”

“…Abnormal transcription factors are major problems. We previously found that a Smek2 deficiency affects lipid metabolism 5 and glucose metabolism 4 . Genes such as Smek2 , which are not fatal if deficient, but can have widespread effects, are associated with the development of non-communicable diseases that manifest late in life.…”

The effects of dietary linoleic acid on reducing serum cholesterol and atherosclerosis development are nullified by a high-cholesterol diet in male and female apoE-deficient mice

“…Such elevated serum cholesterol levels are considered a high-risk pathogenic factor for atherosclerosis (18) . Animal model studies have shown that a high-dietary cholesterol intake increases total serum cholesterol levels in ApoE -/ -mice and ExHC rats (19,20) . Additionally, compositions of dietary fatty acids are also an important factor for serum cholesterol levels.…”

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

“…ExHC rats were established from Sprague-Dawley (SD) rats as a model of diet-induced hypercholesterolemia. 13 Their serum total cholesterol levels increase only when fed a cholesterol-containing diet without dietary bile salt as a result of disorders in carbohydrate metabolism, 14 not of excessive cholesterol synthesis in the liver. Therefore, ExHC rats enables to design more physiological, bile-salt-free dietary condition.…”