Abstract P189: The Prorenin Receptor and its Soluble From Stimulate Hepatic Triglyceride and Cholesterol Metabolism in Male Mice

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Eva Gatineau ◽  
Frédérique Yiannikouris
2018 ◽  
Vol 62 (16) ◽  
pp. 1800315 ◽  
Author(s):  
Lingyu Zhang ◽  
Tiantian Zhang ◽  
Lin Ding ◽  
Jie Xu ◽  
Changhu Xue ◽  
...  

2019 ◽  
Vol 149 (3) ◽  
pp. 416-421 ◽  
Author(s):  
Stephanie G Harshman ◽  
M Kyla Shea ◽  
Xueyan Fu ◽  
Michael A Grusak ◽  
Donald Smith ◽  
...  

ABSTRACTBackgroundMenaquinone-4 (MK4), a vitamin K metabolite, is converted from phylloquinone through a process that requires intermediates of endogenous cholesterol production. Recent evidence suggests that MK4 is involved in kidney function.ObjectiveThe purpose of this study was to determine the effect of atorvastatin treatment on MK4 formation in young and old male mice.MethodsC57BL/6 male mice (4-mo-old and 20-mo-old) were randomly assigned to either a diet containing 300 mg atorvastatin/kg with 3 mg phylloquinone/kg or a control diet containing 3 mg phylloquinone/kg for 8 wk. During week 8, all mice received deuterium-labeled phylloquinone in the diet. Labeled and unlabeled phylloquinone and MK4 in liver, kidney, brain, and intestine were measured by atmospheric pressure chemical ionization LC/MS. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was quantified by reverse transcriptase-PCR. Tissue MK4 and phylloquinone concentrations were compared between atorvastatin treatment groups with use of general linear models.ResultsThere was no age-treatment interaction on MK4 tissue concentrations. In atorvastatin-treated mice, total MK4 and percentage of deuterium-labeled MK4 in kidney were both approximately 45% lower compared to values in mice not given atorvastatin (all P < 0.05). MK4 concentrations did not differ between groups in any other tissue measured.ConclusionIn male mice, atorvastatin reduced endogenous MK4 formation in the kidney, but not other organs. These observations are consistent with our hypothesis that cholesterol metabolism is involved in the generation of MK4. Further research is needed to understand potential regulatory mechanisms and the unique functions of MK4 in the kidney.


Author(s):  
Camilla Pramfalk ◽  
Osman Ahmed ◽  
Matteo Pedrelli ◽  
Mirko E. Minniti ◽  
Serge Luquet ◽  
...  

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1990 ◽  
Author(s):  
Jenny Pape ◽  
Colleen Newey ◽  
Haley Burrell ◽  
Audrey Workman ◽  
Katelyn Perry ◽  
...  

Diabetes and the related disease metabolic syndrome are epidemic in the United States, in part due to a shift in diet and decrease in physical exercise. PAS kinase is a sensory protein kinase associated with many of the phenotypes of these diseases, including hepatic triglyceride accumulation and metabolic dysregulation in male mice placed on a high-fat diet. Herein we provide the first characterization of the effects of western diet (high-fat high-sugar, HFHS) on Per-Arnt-Sim kinase mice (PASK−/−) and the first characterization of both male and female PASK−/− mice. Soleus muscle from the PASK−/− male mice displayed a 2-fold higher oxidative phosphorylation capacity than wild type (WT) on the normal chow diet. PASK−/− male mice were also resistant to hepatic triglyceride accumulation on the HFHS diet, displaying a 2.7-fold reduction in hepatic triglycerides compared to WT mice on the HFHS diet. These effects on male hepatic triglyceride were further explored through mass spectrometry-based lipidomics. The absence of PAS kinase was found to affect many of the 44 triglycerides analyzed, preventing hepatic triglyceride accumulation in response to the HFHS diet. In contrast, the female mice showed resistance to hepatic triglyceride accumulation on the HFHS diet regardless of genotype, suggesting the effects of PAS kinase may be masked.


PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Jun Peng ◽  
Yi Huan ◽  
Qian Jiang ◽  
Su-juan Sun ◽  
Chun-ming Jia ◽  
...  

This study aimed to analyze the effects and potential mechanisms of pioglitazone on triglyceride and cholesterol metabolism in obese diabetic KKAy mice. Pioglitazone was orally administered to KKAy mice over 30 days. Compared to C57BL/6J mice, KKAy mice developed obvious insulin resistance, hepatic steatosis, and hyperlipidemia. Pioglitazone treatment resulted in deteriorated microvesicular steatosis and elevated hepatic triglyceride levels, though plasma triglyceride and free fatty acid levels were reduced by the treatment, compared to nontreated KKAy mice. Plasma alanine aminotransferase activities were also significantly increased. Additionally, pioglitazone increased plasma concentrations of total cholesterol, HDL-cholesterol, and LDL-cholesterol but decreased hepatic cholesterol. Gene expression profiling revealed that pioglitazone stimulated hepatic peroxisome proliferator-activated receptor gamma hyperactivity, and induced the upregulation of adipocyte-specific and lipogenesis-related genes but downregulated of genes involved in triglyceride lipolysis and fatty acidβ-oxidation. Pioglitazone also regulated the genes expression of hepatic cholesterol uptake and excretion, such as low density lipoprotein receptor (LDL-R) and scavenger receptor type-BI (SR-BI). These results suggested that pioglitazone could induce excessive hepatic triglyceride accumulation, thus aggravating liver steatosis and lesions in KKAy mice. Furthermore, pioglitazone may suppress the clearance of serum cholesterol from the liver predominantly through inhibition of LDL-R and SR-BI expression, thus increasing the plasma cholesterol.


Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Eva O Gatineau ◽  
Ming Gong ◽  
Frederique B Yiannikouris

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 56-56
Author(s):  
Kellea Nichols ◽  
Audrey Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Ming Gong ◽  
...  

Abstract Objectives Sex differences exist in obesity associated with cardiovascular disease; however, underlying mechanisms are not completely understood. Previous studies from our laboratory demonstrated that the prorenin receptor (PRR) and its soluble form (sPRR) contribute to adipogenesis and blood pressure control. The present study aimed to determine whether adipose-sPRR stimulated obesity is associated with hypertension and whether it is sex-dependent. Methods Transgenic mice on the C57BL/6 J background were generated expressing the human form of the soluble prorenin receptor (HsPRR) in a Cre-inducible manner. Male mice expressing Cre recombinase under the control of the adiponectin promotor were bred to heterozygote HsPRR/+ female mice to generate mice over-secreting sPRR (adi-HsPRR) and control littermate mice (CTL). The secretion of sPRR in the media doubled in primary adipocytes of adi-HsPRR mice compared to control mice (sPRR. CTL: 3729 ± 805 pg/ml; adi-HsPRR: 6170 ± 1237 pg/ml, P &lt; 0.05) validating the mouse model. Male (CTL = 4; adi-HsPRR = 8) and female mice (CTL = 10; adi-HsPRR = 10) were fed a low-fat (LF) diet or a high-fat diet (HF) for 20 weeks. Body weight was assessed weekly and EchoMRI was examined monthly. Results After 20 weeks on LF diet, adi-HsPRR male mice gained significantly more weight than CTL male mice (CTL: 25.1 ± 0.8 g; adi-HsPRR: 29.0 ± 0.8 g P &lt; 0.05), whereas no significant differences in body weights were observed in female mice. The body composition revealed a significant increase of fat mass, specifically in the epidydimal fat (CTL: 0.35 ± 0.04 g; adi-HsPRR: 0.61 ± 0.07 g, P &lt; 0.05), and lean mass of HsPRR male mice compared to CTL male mice. In contrast, female mice exhibited similar body weights (CTL: 20.6 ± 0.3 g; adi-HsPRR: 20.4 ± 0.4 g) and there was no differences of fat mass or lean mass between CTL and adi-HsPRR female mice. The sex-specific mechanism of sPRR on adipogenesis and blood pressure (by radiotelemetry) with LF and HF diet is currently under investigation. Conclusions Overall, sPRR stimulated body weight gain and fat mass expansion in male mice but not in female mice suggesting that female mice are protected from sPRR induced-hypertrophic effect. Funding Sources R01_HL142969–01 Yiannikouris, PI 07/15/2018–06/30/2022 NIH/NHLBI Title: The role of soluble prorenin receptor in hypertension associated with obesity Role: Ph.D Graduate Student.


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