The Role of a Brain-specific Splice Variant of Ryanodine Receptor Type 1

The ryanodine receptor type 1 (RyR1) is capable of homotetrameric assembly to form a Ca2+ release channel at intracellular Ca2+ storage sites such as endoplasmic reticulum (ER). The mRNA transcript encoding full-length RyR1 is approximately 16kb and is mainly distributed in excitable cells. A 2.4-kb mRNA splice variant from the 3\u27-terminal region of the RyR1 gene coexists specifically in brain together with the full-length form, although the functions of this brain-specific splice variant remain unclear. To investigate the short form of RyR1 in intracellular Ca2+ signaling in brain at the cellular level, we established an experimental system whereby the green fluorescent protein (GFP) -tagged brain-specific variant of RyR1 is coexpressed with the full-length protein in the same cell. Both forms of RyR1 were localized in the ER. Caffeine-induced Ca2+-release activities in cells expressing both the brain-specific and full-length RyR1 were reduced compared to cells expressing only the full-length form of RyR1. These results suggested that coexpression of the brain-specific splice variant of RyR1 with its full-length counterpart modulates intracellular Ca2+ signaling by acting as a dominant-negative subunit of the Ca2+ release channel in a tissue-specific fashion

Vildagliptin Improves Glucose Tolerance and Decreases Plasma Triglycerides in Sprague-Dawley Rats

The number of patients with lifestyle-related diseases, including type 2 diabetes, is increasing. The onset of type 2 diabetes can be prevented by dietary and exercise interventions, as well as drug therapy. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have attracted attention recently as treatments for diabetes, and incretin hormones have been reported to have a protective effect on pancreatic β-cells. It is not clear whether vildagliptin (VIL) can prevent the progression of lifestyle-related disease. Thus, in the present study, Sprague-Dawley rats were fed a high-fat diet with sucrose water (HFDS) to determine whether VIL could inhibit deterioration in glucose tolerance and improve other biomarkers of lipid disorder. Four-month-old male Sprague-Dawley rats were divided into three groups (n = 7 in each group); one group was fed a normal diet for 4 months, whereas the remaining two groups were fed the HFDS, with or without VIL for 4 months. When rats were 7 months of age, they were subjected to an intraperitoneal glucose tolerance test (IPGTT); biomarkers of lipid disorder were measured in 8-month-old rats. There was a decrease in the glucose spike in the IPGTT 10min after loading in the HFDS + VIL group and plasma triglyceride (TG) levels were significantly lower in these rats compared with the HFDS group. The decreased TG levels in HFDS + VIL rats were accompanied by decreases in plasma chylomicron levels. These results suggest that VIL can prophylactically inhibit decreases in pancreatic β-cell function in type 2 diabetes and reduce the risk of cardiovascular disease due to high TG levels. Thus, VIL administration may contribute to the prevention of lifestyle-related disease

Visceral Fat Accumulation is Associated with Oxidative Stress and Increased Matrix Metalloproteinase-9 Expression in Atherogenic Factor-overlapped Model Rats

Visceral fat accumulation in lifestyle-related diseases increases the risk of atherosclerosis. Matrix metalloproteinases (MMPs) play an important role in the progression of atherosclerosis. We examined atherogenic factor-overlapped model rats to clarify the relationships among visceral fat, oxidative stress, and MMPs. We used four groups of male, 11-month-old, spontaneously hypertensive hyperlipidemic rats (SHHRs) or Sprague-Dawley (SD) rats. Animals were fed either a diet of high fat and 30% sucrose solution (HFDS) or a normal diet (ND) ad libitum for 6 months. The visceral fat weight increased by approximately three fold in SHHR-HFDS compared to SHHR-ND. The oxidative stress marker in plasma and MMP-9 mRNA expression in white blood cells increased in SHHR-HFDS compared to the other groups. A correlation was determined between oxidative stress and visceral fat or MMP-9 mRNA in all rats. Lipid deposition and immunostaining of CD68 and MMP-9 were observed mainly in the intima of aorta in SHHR-HFDS, while tissue inhibitor of metalloproteinase-1 mRNA expression decreased in both SHHR groups. The findings suggested that increased oxidative stress due to the visceral fat accumulation induced MMP-9 expression and macrophage accumulation in the intima of aorta in lifestyle-related disease model rats