Mutation in Smek2 Regulating Hepatic Glucose Metabolism Causes Hypersarcosinemia and Hyperhomocysteinemia in Rats

Overview

Journal Sci Rep

Specialty Science

Date 2023 Feb 22

PMID 36810603

Authors

Yasutake Tanaka

Michio Kawano

Sawako Nakashima

Chisato Yamaguchi

Makoto Asahina

Mai Sakamoto

Bungo Shirouchi

Kousuke Tashiro

Katsumi Imaizumi

Masao Sato

Affiliations

Soon will be listed here.

Abstract

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 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.

References

Drobny A, Meloh H, Wachtershauser E, Hellmann B, Mueller A, Van der Klis J . Betaine-rich sugar beet molasses protects from homocysteine-induced reduction of survival in Caenorhabditis elegans. Eur J Nutr. 2019; 59(2):779-786. DOI: 10.1007/s00394-019-01944-3. View

Hoffmann L, Brauers G, Gehrmann T, Haussinger D, Mayatepek E, Schliess F . Osmotic regulation of hepatic betaine metabolism. Am J Physiol Gastrointest Liver Physiol. 2013; 304(9):G835-46. DOI: 10.1152/ajpgi.00332.2012. View

Chao C, McKnight K, Cox K, Chang A, Kim S, Feldman B . Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations. PLoS One. 2015; 10(2):e0118449. PMC: 4338276. DOI: 10.1371/journal.pone.0118449. View

Sreekumar A, Poisson L, Rajendiran T, Khan A, Cao Q, Yu J . Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009; 457(7231):910-4. PMC: 2724746. DOI: 10.1038/nature07762. View

Altarejos J, Montminy M . CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011; 12(3):141-51. PMC: 4324555. DOI: 10.1038/nrm3072. View

van der Veen J, Kennelly J, Wan S, Vance J, Vance D, Jacobs R . The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim Biophys Acta Biomembr. 2017; 1859(9 Pt B):1558-1572. DOI: 10.1016/j.bbamem.2017.04.006. View

Postma A, van de Meerakker J, Mathijssen I, Barnett P, Christoffels V, Ilgun A . A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. 2008; 102(11):1433-42. DOI: 10.1161/CIRCRESAHA.107.168294. View

Asahina M, Haruyama W, Ichida Y, Sakamoto M, Sato M, Imaizumi K . Identification of SMEK2 as a candidate gene for regulation of responsiveness to dietary cholesterol in rats. J Lipid Res. 2008; 50(1):41-6. DOI: 10.1194/jlr.M800135-JLR200. View

Asahina M, Sato M, Imaizumi K . Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats. J Lipid Res. 2005; 46(10):2289-94. DOI: 10.1194/jlr.M500257-JLR200. View

10.

Harding C, Williams P, Pflanzer D, Colwell R, Lyne P, Wolff J . sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis. Proc Natl Acad Sci U S A. 1992; 89(7):2644-8. PMC: 48718. DOI: 10.1073/pnas.89.7.2644. View

11.

Fan Q, Liu Z, Shen C, Li H, Ding J, Jin F . Microarray study of gene expression profile to identify new candidate genes involved in the molecular mechanism of leptin-induced knee joint osteoarthritis in rat. Hereditas. 2017; 155:4. PMC: 5496599. DOI: 10.1186/s41065-017-0039-z. View

12.

Levy H, Coulombe J, Benjamin R . Massachusetts Metabolic Disorders Screening Program: III. Sarcosinemia. Pediatrics. 1984; 74(4):509-13. View

13.

Lyu J, Jho E, Lu W . Smek promotes histone deacetylation to suppress transcription of Wnt target gene brachyury in pluripotent embryonic stem cells. Cell Res. 2011; 21(6):911-21. PMC: 3203701. DOI: 10.1038/cr.2011.47. View

14.

Allen R, Stabler S, Lindenbaum J . Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism. 1993; 42(11):1448-60. DOI: 10.1016/0026-0495(93)90198-w. View

15.

Tanaka Y, Nagao K, Nakagiri H, Nagaso T, Iwasa Y, Mori H . Unavailability of liver triacylglycerol increases serum cholesterol concentration induced by dietary cholesterol in exogenously hypercholesterolemic (ExHC) rats. Lipids Health Dis. 2014; 13:19. PMC: 3902423. DOI: 10.1186/1476-511X-13-19. View

16.

Hao Y, Chun A, Cheung K, Rashidi B, Yang X . Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2007; 283(9):5496-509. DOI: 10.1074/jbc.M709037200. View

17.

Yoon Y, Lee M, Ryu D, Kim J, Ma H, Seo W . Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. Proc Natl Acad Sci U S A. 2010; 107(41):17704-9. PMC: 2955085. DOI: 10.1073/pnas.1012665107. View

18.

Tohge T, Nishiyama Y, Hirai M, Yano M, Nakajima J, Awazuhara M . Functional genomics by integrated analysis of metabolome and transcriptome of Arabidopsis plants over-expressing an MYB transcription factor. Plant J. 2005; 42(2):218-35. DOI: 10.1111/j.1365-313X.2005.02371.x. View

19.

Parker D, Ferreri K, Nakajima T, LaMorte V, Evans R, Koerber S . Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism. Mol Cell Biol. 1996; 16(2):694-703. PMC: 231049. DOI: 10.1128/MCB.16.2.694. View

20.

Folch J, Lees M, SLOANE STANLEY G . A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957; 226(1):497-509. View