![]() 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. This deletion leads to disrupted SMEK2 protein function that is not fatal in rats. The ExHC rats have a 10-bp deletion mutation in the coding region of the Smek2 gene 3. Further investigation identified a responsible gene, suppressor of mek1 (Dictyostelium) homolog 2 ( Smek2) from the Dihc2 region 3. We previously conducted linkage analysis of ExHC with Brown Norway (BN) rats as a control to identify the female-specific responsible loci Dihc1 on chromosome.5 and a unisex-responsible locus Dihc2, 4.1 Mbp region at the 3′ end, on chromosome.14 2, 3. Although their serum cholesterol levels are within the normal range without dietary cholesterol, they rapidly develop hypercholesterolemia when fed with a diet containing cholesterol. Results suggest that homocysteine metabolism rendered fragile by a shortage of betaine results in homocysteinemia, and that Smek2 dysfunction causes abnormalities in sarcosine and homocysteine metabolism.Įxogenous hypercholesterolemic (ExHC) rats serve as a model of diet-induced hypercholesterolemia (DIHC) 1. ![]() ![]() The mRNA expression of Bhmt, a homocysteine metabolic enzyme and the hepatic content of betaine (trimethylglycine), a methyl donor for homocysteine methylation were low in ExHC rats. The ExHC rats with dysfunctional Sardh developed hypersarcosinemia and homocysteinemia, a risk factor for atherosclerosis, with or without dietary cholesterol. Sarcosine dehydrogenase demethylates sarcosine, a byproduct of homocysteine metabolism. Microarray analysis revealed that Smek2 dysfunction leads to extremely low sarcosine dehydrogenase ( Sardh) expression in the liver of ExHC rats. We used microarrays to investigate Smek2 functions with ExHC and ExHC.BN- Dihc2 BN congenic rats that harbor a non-pathological Smek2 allele from Brown-Norway rats on an ExHC background. The intracellular role of Smek2 remains obscure. A deletion mutation in Smek2 leads to DIHC via impaired glycolysis in the livers of ExHC rats. Suppressor of mek1 (Dictyostelium) homolog 2 ( Smek2), was identified as one of the responsible genes for diet-induced hypercholesterolemia (DIHC) of exogenously hypercholesterolemic (ExHC) rats. ![]()
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