Stimulation of hepatic mitochondrial calcium transport by elevated plasma insulin concentrations.
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ABSTRACT:
SUBMITTER: Dorman DM
PROVIDER: S-EPMC1165753 | biostudies-other | 1975 Sep
REPOSITORIES: biostudies-other
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2022-03-07 | GSE179719 | GEO
Project description:Background: Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism affecting the synthesis or breakdown of glycogen in the liver. This study, for the first time, systematically assessed vitamin B12 status in a large cohort of hepatic GSD patients. Methods: Plasma vitamin B12, total plasma homocysteine (tHcy) and methylmalonic acid concentrations were measured in 44 patients with hepatic GSDs and compared to 42 healthy age- and gender-matched controls. Correlations of vitamin B12 status with different disease markers of GSDs (including liver transaminase activities and triglycerides) as well as the vitamin B12 intake were studied. Results: GSD patients had significantly higher plasma vitamin B12 concentrations than healthy controls (p = 0.0002). Plasma vitamin B12 concentration remained elevated in GSD patients irrespective of vitamin B12 intake. Plasma vitamin B12 concentrations correlated negatively with triglyceride levels, whereas no correlations were detected with liver transaminase activities (GOT and GPT) in GSD patients. Merging biomarker data of healthy controls and GSD patients showed a positive correlation between vitamin B12 status and liver function, which suggests complex biomarker associations. A combined analysis of biomarkers permitted a reliable clustering of healthy controls versus GSD patients. Conclusions: Elevated plasma concentration of vitamin B12 (irrespective of B12 intake) is a common finding in patients with hepatic GSD. The negative correlation of plasma vitamin B12 with triglyceride levels suggests an influence of metabolic control on the vitamin B12 status of GSD patients. Elevated vitamin B12 was not correlated with GOT and GPT in our cohort of GSD patients. Merging of data from healthy controls and GSD patients yielded positive correlations between these biomarkers. This apparent dichotomy highlights the intrinsic complexity of biomarker associations and argues against generalizations of liver disease and elevated vitamin B12 in blood. Further studies are needed to determine whether the identified associations are causal or coincidental, and the possible impact of chronically elevated vitamin B12 on GSD.
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Project description:IntroductionThe impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis.MethodsPlasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression.Resultsp-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (β = 0.75, P < .01), NfL (β = 0.32, P < .01), and t-tau (β = 0.31, P < .01), but not GFAP (β = -0.01, P = .88) or UCHL1 (β = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (β = -0.18, P < .01), NfL (β = -0.22, P < .01), GFAP (β = -0.17, P < .05), t-tau (β = -0.20, P = .02), and UCHL1 (β = -0.15, P = .09).ConclusionsElevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.
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Project description:Purpose: To reveal the mechanism of mitochondrial DNA methylation in the progression of fatty liver and insulin resistance. Methods: Liver mitochondrial DNA bisulfite-sequencing of high-fat diet (HFD) and db/db diabetic mice were using Illumina 4000. Western blot, real-time PCR and confocal microscopy were used for further biochemical validation. Results: In the present study, we found increased mitochondrial localization of DNA methyltransferase 1 (DNMT1) in the liver of high-fat diet (HFD) and db/db diabetic mice. Whole genome bisulfite sequencing of mouse liver mtDNA revealed significant increase of cytosine methylation frequencies including CG, CHG and CHH on both L and H-strand in the diabetic mice comparing with normal control, and ND6 showed the most dramatic increase on the L-strand. Conclusions: Our present study suggests an epigenetic regulatory of mitochondrial homeostasis and insulin sensitivity by DNMT1, providing novel therapeutic targets for the prevention and treatment of fatty liver and type 2 diabetes.
2021-03-27 | GSE111996 | GEO
Project description:ObjectiveTransport of Ca2+ into pancreatic β cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ transport in intact cells. We examined the consequences of deficiency of the accessory protein MICU2 in rat and human insulin-secreting cells and mouse islets.MethodssiRNA silencing of Micu2 in the INS-1 832/13 and EndoC-βH1 cell lines was performed; Micu2-/- mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed.ResultsSilencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-βH1 cells. The Micu2-/- mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-βH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ uptake, perturbed mitochondrial function illustrated by absent mitochondrial membrane hyperpolarization and lowering of the ATP/ADP ratio in response to elevated glucose. Despite the loss of mitochondrial Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels.ConclusionsMICU2 plays a critical role in β cell mitochondrial Ca2+ uptake. β cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS.
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