Abstract:G protein-coupled receptors (GPCRs) comprise the largest group of membrane receptors in eukaryotic genomes and collectively they regulate nearly all cellular processes.Despite the widely recognized importance of this class of proteins, many GPCRs remain understudied. G protein-coupled receptor 27 (Gpr27) is an orphan GPCR that displays high conservation during vertebrate evolution. Although, GPR27 is known to be expressed in tissues that regulate metabolism including the pancreas, skeletal muscle, and adipose … Show more
“…None of these genes had a highly conserved non-synonymous variant that is expected to be damaging. Foxp1 has previously been shown to regulate hepatic glucose homeostasis 45 , and insulin stimulated glucose uptake 46 , making it a strong candidate, although both Gpr27 47 , 48 and Prok2 49 also play a role in glucose related phenotypes. Figure 7 Genome scans for select intermediary serum biochemistry measures.…”
Section: Resultsmentioning
confidence: 99%
“…Although no variants were found in Foxp1 , this gene falls directly under the peak marker and Foxp1 has been shown to regulate hepatic glucose homeostasis 45 and insulin stimulated glucose uptake 46 . Both Gpr27 47 , 48 and Prok2 49 , which fall within the wider confidence interval are also potential candidates within this region. No significant associations were observed for serum creatinine and BUN.…”
Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.
“…None of these genes had a highly conserved non-synonymous variant that is expected to be damaging. Foxp1 has previously been shown to regulate hepatic glucose homeostasis 45 , and insulin stimulated glucose uptake 46 , making it a strong candidate, although both Gpr27 47 , 48 and Prok2 49 also play a role in glucose related phenotypes. Figure 7 Genome scans for select intermediary serum biochemistry measures.…”
Section: Resultsmentioning
confidence: 99%
“…Although no variants were found in Foxp1 , this gene falls directly under the peak marker and Foxp1 has been shown to regulate hepatic glucose homeostasis 45 and insulin stimulated glucose uptake 46 . Both Gpr27 47 , 48 and Prok2 49 , which fall within the wider confidence interval are also potential candidates within this region. No significant associations were observed for serum creatinine and BUN.…”
Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.
“…The fish did not show high FBS with normal diet, but a significant increase with a high fat diet, as we see in human T2DM state. The fish were also resistant to insulin injection, suggesting insulin resistance condition and a solid model for subsequent studies of T2DM (Nath et al, 2020 ).…”
Section: Methods/models Of Inducing Hyperglycemia In Zebrafishmentioning
confidence: 99%
“…In human, high fasting blood glucose is usually the first indicator of T2DM existence and a clue to further investigations. In the reviewed studies, fasting blood glucose elevation (Gleeson et al, 2007 ; Connaughton et al, 2016 ), post-high content diet feeding blood glucose elevation (Yang et al, 2018 ), post-prandial glucose elevation (Nath et al, 2020 ), or whole larval glucose elevation (Karanth et al, 2016 ) are reported as the primary indicator of T2DM existence possibility.…”
Despite extensive studies on type 2 diabetes mellitus (T2DM), there is no definitive cure, drug, or prevention. Therefore, for developing new therapeutics, proper study models of T2DM is necessary to conduct further preclinical researches. Diabetes has been induced in animals using chemical, genetic, hormonal, antibody, viral, and surgical methods or a combination of them. Beside different approaches of diabetes induction, different animal species have been suggested. Although more than 85% of articles have proposed rat (genus Rattus) as the proper model for diabetes induction, zebrafish (Danio rerio) models of diabetes are being used more frequently in diabetes related studies. In this systematic review, we compare different aspects of available methods of inducing hyperglycemia referred as T2DM in zebrafish by utilizing a scoring system. Evaluating 26 approved models of T2DM in zebrafish, this scoring system may help researchers to compare different T2DM zebrafish models and select the best one regarding their own research theme. Eventually, glyoxalase1 (glo1−/−) knockout model of hyperglycemia achieved the highest score. In addition to assessment of hyperglycemic induction methods in zebrafish, eight most commonly proposed diabetic induction approval methods are suggested to help researchers confirm their subsequent proposed models.
“…In addition, the expression pattern of these genes appear to be comparable to humans. 37 38 39 40 41 One important differences in lipid metabolism between zebrafish and humans is that zebrafish only produces full-length apoB (apoB-100) and lack truncated apoB (apoB-48). Therefore, despite their structural similarity to humans, zebrafish chylomicrons are coated with apoB-100 which renders them less likely to undergo rapid clearance by the liver and mature as LDL.…”
Section: Lipid Metabolism In Zebrafish and Humansmentioning
Dyslipidemia related diseases such as hyperlipidemia and atherosclerosis are the leading cause of death in humans. While cellular and molecular basis on the pathophysiology of dyslipidemia has been extensively investigated over decades, we still lack comprehensive understanding on the etiology of dyslipidemia due to the complexity and the innate multimodality of the diseases. While mouse has been the model organism of choice to investigate the pathophysiology of human dyslipidemia, zebrafish, a small freshwater fish which has traditionally used to study vertebrate development, has recently emerged as an alternative model organism. In this review, we will provide comprehensive perspective on zebrafish as a model organism for human dyslipidemia; we will discuss the attributes of zebrafish as a model, and compare the lipid metabolism in zebrafish and humans. In addition, we will summarize current landscape of zebrafish-based dyslipidemia research.
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