TY  - JOUR
A1  - Bär, Ludmilla
A1  - Feger, Martina
A1  - Fajol, Abul
A1  - Klotz, Lars-Oliver
A1  - Zeng, Shufei
A1  - Lang, Florian
A1  - Hocher, Berthold
A1  - Föller, Michael
T1  - Insulin suppresses the production of fibroblast growth factor 23 (FGF23)
JF  - Proceedings of the National Academy of Sciences of the United States of America
N2  - Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.
KW  - PI3K
KW  - PKB/Akt
KW  - Klotho
KW  - phosphate
Y1  - 2018
U6  - https://doi.org/10.1073/pnas.1800160115
SN  - 0027-8424
VL  - 115
IS  - 22
SP  - 5804
EP  - 5809
PB  - National Acad. of Sciences
CY  - Washington
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Lu, Yong-Ping
A1  - Reichetzeder, Christoph
A1  - Zhang, Xiaoli
A1  - Tsuprykov, Oleg
A1  - Rahnenführer, Jan
A1  - Xie, Li
A1  - Li, Jian
A1  - Hu, Liang
A1  - Krämer, Bernhard K.
A1  - Hasan, Ahmed A.
T1  - Paternal eNOS deficiency in mice affects glucose homeostasis and liver glycogen in male offspring without inheritance of eNOS deficiency itself
JF  - Diabetologia
N2  - Aims/hypothesis It was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring's phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency. Methods Heterozygous (+/-) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents. Results Global sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/- eNOS fathers. Wild-type male but not female offspring of +/- eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/- eNOS fathers. The endocrine pancreas in wild-type offspring was not affected. <br /> Conclusions/interpretation Our study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/- eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes.
KW  - eNOS
KW  - Glucocorticoid receptor
KW  - Insulin resistance
KW  - Paternal programming;
KW  - PGC1a
Y1  - 2022
U6  - https://doi.org/10.1007/s00125-022-05700-x
SN  - 0012-186X
SN  - 1432-0428
VL  - 65
IS  - 7
SP  - 1222
EP  - 1236
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Tao, Ting
A1  - Su, Qiongli
A1  - Xu, Simeng
A1  - Deng, Jun
A1  - Zhou, Sichun
A1  - Zhuang, Yu
A1  - Huang, Yanjun
A1  - He, Caimei
A1  - He, Shanping
A1  - Peng, Mei
A1  - Hocher, Berthold
A1  - Yang, Xiaoping
T1  - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis
JF  - Journal of cellular physiology
N2  - Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.
KW  - bladder cancer cells
KW  - FASN
KW  - p-AKT
KW  - PKM2
KW  - p-mTOR
KW  - SREBP-1c
Y1  - 2018
U6  - https://doi.org/10.1002/jcp.27129
SN  - 0021-9541
SN  - 1097-4652
VL  - 234
IS  - 3
SP  - 3088
EP  - 3104
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Tsuprykov, Oleg
A1  - Yang, Xiaoping
A1  - Hocher, Berthold
T1  - Paternal programming of offspring cardiometabolic diseases in later life
JF  - Journal of hypertension
KW  - cardiometabolic diseases
KW  - epigenetics
KW  - offspring
KW  - paternal programming
KW  - spermatogenesis
KW  - transgenerational effects
Y1  - 2016
U6  - https://doi.org/10.1097/HJH.0000000000001051
SN  - 0263-6352
SN  - 1473-5598
VL  - 34
SP  - 2111
EP  - 2126
PB  - Wiley-Blackwell
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Scholze, Alexandra
A1  - Liu, Ying
A1  - Pedersen, Lise
A1  - Xia, Shengqiang
A1  - Roth, Heinz J.
A1  - Hocher, Berthold
A1  - Rasmussen, Lars Melholt
A1  - Tepel, Martin
T1  - Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23
JF  - The journal of clinical endocrinology & metabolism
N2  - Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study.
 Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol.
 Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency).
 Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly.
 Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1.
 Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho.
 Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations.
Y1  - 2014
U6  - https://doi.org/10.1210/jc.2013-4171
SN  - 0021-972X
SN  - 1945-7197
VL  - 99
IS  - 5
SP  - E855
EP  - E861
PB  - Endocrine Society
CY  - Washington
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Shen, Jinhua
A1  - Zhang, Xiaoli
A1  - Peng, Yangqin
A1  - Zhang, Qin
A1  - Hu, Liang
A1  - Reichetzeder, Christoph
A1  - Zeng, Suimin
A1  - Li, Jing
A1  - Tian, Mei
A1  - Gong, Fei
A1  - Lin, Ge
A1  - Hocher, Berthold
T1  - Risk factors associated with preterm birth after IVF/ICSI
JF  - Scientific reports
N2  - In vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is associated with an increased risk of preterm (33rd-37th gestational week) and early preterm birth (20th-32nd gestational week). The underlying general and procedure related risk factors are not well understood so far. 4328 infertile women undergoing IVF/ICSI were entered into this study. The study population was divided into three groups: (a) early preterm birth group (n = 66), (b) preterm birth group (n = 675) and (c) full-term birth group (n = 3653). Odds for preterm birth were calculated by stepwise multivariate logistic regression analysis. We identified seven independent risk factors for preterm birth and four independent risk factors for early preterm birth. Older (> 39) or younger (< 25) maternal age (OR: 1.504, 95% CI 1.108-2.042, P = 0.009; OR: 2.125, 95% CI 1.049-4.304, P = 0.036, respectively), multiple pregnancy (OR: 9.780, 95% CI 8.014-11.935, P < 0.001; OR: 8.588, 95% CI 4.866-15.157, P < 0.001, respectively), placenta previa (OR: 14.954, 95% CI 8.053-27.767, P < 0.001; OR: 16.479, 95% CI 4.381-61.976, P < 0.001, respectively), and embryo reduction (OR: 3.547, 95% CI 1.736-7.249, P = 0.001; OR: 7.145, 95% CI 1.990-25.663, P = 0.003, respectively) were associated with preterm birth and early preterm birth, whereas gestational hypertension (OR: 2.494, 95% CI 1.770-3.514, P < 0.001), elevated triglycerides (OR: 1.120, 95% CI 1.011-1.240, P = 0.030) and shorter activated partial thromboplastin time (OR: 0.967, 95% CI 0.949-0.985, P < 0.001) were associated only with preterm birth. In conclusion, preterm and early preterm birth risk factors in patients undergoing assisted IVF/ICSI are in general similar to those in natural pregnancy. The lack of some associations in the early preterm group was most likely due to the lower number of early preterm birth cases. Only embryo reduction represents an IVF/ICSI specific risk factor.
Y1  - 2022
U6  - https://doi.org/10.1038/s41598-022-12149-w
SN  - 2045-2322
VL  - 12
IS  - 1
PB  - Nature Research
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Xiong, Yingquan
A1  - Delic, Denis
A1  - Zeng, Shufei
A1  - Chen, Xin
A1  - Chu, Chang
A1  - Hasan, Ahmed A.
A1  - Krämer, Bernhard K.
A1  - Klein, Thomas
A1  - Yin, Lianghong
A1  - Hocher, Berthold
T1  - Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy-effects of salt, ARB, DPP4 inhibitor and SGLT2 blocker
JF  - BMC nephrology
N2  - Background Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. Methods We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. Results In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. Conclusions Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.
KW  - SARS CoV-2 host factors
KW  - 5/6 nephrectomy
KW  - High-salt diet
KW  - ARB
KW  - DPP4 inhibitor
KW  - SGLT2 blocker
Y1  - 2022
U6  - https://doi.org/10.1186/s12882-022-02747-1
SN  - 1471-2369
VL  - 23
IS  - 1
PB  - Springer Nature
CY  - London
ER  -