title: Decreased cystathionine-γ-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients.
abstract: The liver plays a major role in the formation of H2S, a novel signaling molecule. Diabetes is associated with lower blood levels of H2S. This study investigated the activities of cystathionine-γ-lyase (CSE, the enzyme that catalyzes H2S formation) in livers of type 1 diabetic (T1D) animals and in peripheral blood mononuclear cells (PBMC) isolated from T1D patients. T1D is associated with both hyperketonemia (acetoacetate and β-hydroxybutyrate) and hyperglycemia. This study also examined the role of hyperglycemia and hyperketonemia per se in decreased CSE activity using U937 monocytes and PBMC isolated from healthy subjects. Livers from streptozotocin-treated T1D rats demonstrated a significantly higher reactive oxygen species production, lower CSE protein expression and activity, and lower H2S formation compared with those of controls. Studies with T1D patients showed a decrease in CSE protein expression and activity in PBMC compared with those of age-matched normal subjects. Cell culture studies demonstrated that high glucose (25 mm) and/or acetoacetate (4 mm) increased reactive oxygen species, decreased CSE mRNA expression, protein expression, and enzymatic activity, and reduced H2S levels; however, β-hydroxybutyrate treatment had no effect. A similar effect, which was also observed in PBMC treated with high glucose alone or along with acetoacetate, was prevented by vitamin D supplementation. Studies with CSE siRNA provide evidence for a relationship between impaired CSE expression and reduced H2S levels. This study demonstrates for the first time that both hyperglycemia and hyperketonemia mediate a reduction in CSE expression and activity, which can contribute to the impaired H2S signaling associated with diabetes.
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Manna
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103.
authors.forename: Neslihan
authors.initials: N
authors.lastname: Gungor
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103.
authors.forename: Robert
authors.initials: R
authors.lastname: McVie
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103. Electronic address: sjain@lsuhsc.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology*; D020868:Gene Silencing; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D009000:Monocytes / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020298:U937 Cells
chemical_list: D034741:RNA, Small Interfering; D003542:Cystathionine gamma-Lyase
keywords: Acetoacetate; Diabetes; Glucose; Hydrogen Sulfide; Ketone Bodies