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

• Published in: Scientific reports Vol. 13; no. 1; p. 3053
• Main Authors: Tanaka, Yasutake, Kawano, Michio, Nakashima, Sawako, Yamaguchi, Chisato, Asahina, Makoto, Sakamoto, Mai, Shirouchi, Bungo, Tashiro, Kousuke, Imaizumi, Katsumi, Sato, Masao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/737; 692/4020/4021/1607; 692/4020/4021/288; 692/699/317; Amino Acid Metabolism, Inborn Errors - genetics; Animals; Arteriosclerosis; Betaine; Betaine - metabolism; Betaine-homocysteine S-methyltransferase; Cholesterol; Dehydrogenase; Dehydrogenases; Gene deletion; Gene expression; Glucose - metabolism; Glycolysis; Homocysteine; Homocysteine - metabolism; Humanities and Social Sciences; Hypercholesterolemia; Hypercholesterolemia - genetics; Hyperhomocysteinemia; Hyperhomocysteinemia - complications; Liver; Liver - metabolism; Metabolism; multidisciplinary; Mutation; Phosphoprotein Phosphatases - genetics; Rats; Rats, Inbred BN; Risk factors; Sarcosine; Sarcosine - metabolism; Sarcosine dehydrogenase; Sarcosine Dehydrogenase - deficiency; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-26115-z

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. A deletion mutation in Smek2 leads to DIHC via impaired glycolysis in the livers of ExHC rats. The intracellular role of Smek2 remains obscure. 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. Microarray analysis revealed that Smek2 dysfunction leads to extremely low sarcosine dehydrogenase ( Sardh ) expression in the liver of ExHC rats. Sarcosine dehydrogenase demethylates sarcosine, a byproduct of homocysteine metabolism. The ExHC rats with dysfunctional Sardh developed hypersarcosinemia and homocysteinemia, a risk factor for atherosclerosis, with or without dietary cholesterol. 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. 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.