scholarly journals Pemafibrate Protects against Fatty Acid-Induced Nephropathy by Maintaining Renal Fatty Acid Metabolism

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 372
Author(s):  
Daiki Aomura ◽  
Makoto Harada ◽  
Yosuke Yamada ◽  
Takero Nakajima ◽  
Koji Hashimoto ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Male Mice ◽  
Histological Findings ◽  
Tubular Injury ◽  
Wild Type ◽  
Wild Type Male ◽  
And Oxidative Stress

As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.

scholarly journals Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Hongyan Ren ◽  
Wei Xiao ◽  
Xingliang Qin ◽  
Gangzhi Cai ◽  
Hao Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Muscle Growth ◽  
Subcutaneous Fat ◽  
Fat Deposition ◽  
Wild Type ◽  
Binding Prediction ◽  
Stearoyl Coa Desaturase

Abstract Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.

scholarly journals Global Gene Expression Profiling in PPAR-γAgonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Daisuke Yoshihara ◽  
Masanori Kugita ◽  
Tamio Yamaguchi ◽  
Harold M. Aukema ◽  
Hiroki Kurahashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Interstitial Fibrosis ◽  
Global Gene Expression ◽  
Polycystic Kidney

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γagonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism.

Abstract P028: Activation Of The Renin-angiotensin System Drives Renal Metabolic Abnormalities In Diabetic Nephropathy

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Kengo Azushima ◽  
Jean Paul Kovalik ◽  
Jianhong Ching ◽  
Susan B Gurley ◽  
Thomas M Coffman
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Renin Angiotensin System ◽  
Tca Cycle ◽  
High Grade ◽  
Wild Type ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Mitochondrial Fatty Acid

Activation of the renin-angiotensin system (RAS) is a major contributor to the pathogenesis of diabetic nephroathy (DN). However, the precise mechanisms of renoprotection associated with RAS blockade in DN are not entirely clear. The aim of this study is to examine whether metabolic effects of RAS blockade might contribute to renoprotection. We utilized a mouse model of DN combining severe type I diabetes (the Akita mutation) with a single-copy renin transgene (ReninTG) driven by the albumin promoter. Akita-ReninTG mice on a 129/Sv background (DN-susceptible mice) develop clinical features of human DN including high-grade albuminuria, renal interstitial inflammation and glomerulosclerosis, while Akita-ReninTG mice on a C57BL/6 background (DN-resistant mice) do not develop significant kidney disease. These two experimental groups were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks, and metabolic profiles in kidney tissues were examined using a targeted metabolomics assay. The DN-susceptible mice exhibited high-grade albuminuria that was significantly attenuated by ARB (Vehicle vs ARB: 1480±562 vs 193±42 μg/day, p =0.045), while DN-resistant mice had minimal albuminuria that was not affected by ARB (Vehicle vs ARB: 80±14 vs 75±14 μg/day, p =0.801). The metabolomics profiles of the DN-resistant mice were similar to C57BL/6 wild-type controls. By contrast, DN-susceptible mice exhibited broad reductions in even-chain acyl-carnitines and an abnormal profile of TCA cycle intermediates compared to 129/Sv wild-type controls, suggesting substantial impairments of renal mitochondrial fuel oxidation including altered fatty acid metabolism. RAS blockade had broad effects to correct this profile by increasing acetyl-carnitines generated from acetyl-CoA and concomitantly normalizing expression of genes associated with mitochondrial fatty acid metabolism including PPAR-α, PGC-1α, CPT1 and CPT2. ARB treatment restored TCA cycle activity to normal. These findings suggest that effects of RAS blockade re-establish normal fuel metabolism and mitochondrial fatty acid oxidation in kidney and may contribute to renoprotection.

scholarly journals The link between phenotype and fatty acid metabolism in advanced chronic kidney disease

2017 ◽  
Vol 32 (7) ◽  
pp. 1154-1166 ◽  
Author(s):  
Dan-Qian Chen ◽  
Hua Chen ◽  
Lin Chen ◽  
Nosratola D. Vaziri ◽  
Ming Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Advanced Chronic Kidney Disease

Folate depletion changes gene expression of fatty acid metabolism, DNA synthesis, and circadian cycle in male mice

2012 ◽  
Vol 32 (2) ◽  
pp. 124-132 ◽  
Author(s):  
Jacques Champier ◽  
Francine Claustrat ◽  
Nicolas Nazaret ◽  
Michelle Fèvre Montange ◽  
Bruno Claustrat
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Dna Synthesis ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Circadian Cycle ◽  
Male Mice ◽  
Folate Depletion

scholarly journals RiboTag translatomic profiling of Drosophila oenocytes under aging and oxidative stress

2018 ◽  
Author(s):  
Kerui Huang ◽  
Wenhao Chen ◽  
Fang Zhu ◽  
Hua Bai
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Stress Response ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Fat Body ◽  
Mapk Signaling ◽  
Age Related ◽  
And Oxidative Stress

AbstractBackgroundAging is accompanied with loss of tissue homeostasis and accumulation of cellular damages. As one of the important metabolic centers, aged liver shows altered lipid metabolism, impaired detoxification pathway, increased inflammation and oxidative stress response. However, the mechanisms for these age-related changes still remain unclear. In fruit flies, Drosophila melanogaster, liver-like functions are controlled by two distinct tissues, fat body and oenocytes. Although the role of fat body in aging regulation has been well studied, little is known about how oenocytes age and what are their roles in aging regulation. To address these questions, we used cell-type-specific ribosome profiling (RiboTag) to study the impacts of aging and oxidative stress on oenocyte translatome in Drosophila.ResultsWe show that aging and oxidant paraquat significantly increased the levels of reactive oxygen species (ROS) in adult oenocytes of Drosophila, and aged oenocytes exhibited reduced sensitivity to paraquat treatment. Through RiboTag sequencing, we identified 3324 and 949 differentially expressed genes in oenocytes under aging and paraquat treatment, respectively. Aging and paraquat exhibit both shared and distinct regulations on oenocyte translatome. Among all age-regulated genes, mitochondrial, proteasome, peroxisome, fatty acid metabolism, and cytochrome P450 pathways were down-regulated, whereas DNA replication and glutathione metabolic pathways were up-regulated. Interestingly, most of the peroxisomal genes were down-regulated in aged oenocytes, including peroxisomal biogenesis factors and beta-oxidation genes. Further analysis of the oenocyte translatome showed that oenocytes highly expressed genes involving in liver-like processes (e.g., ketogenesis). Many age-related transcriptional changes in oenocytes are similar to aging liver, including up-regulation of Ras/MAPK signaling pathway and down-regulation of peroxisome and fatty acid metabolism.ConclusionsOur oenocyte-specific translatome analysis identified many genes and pathways that are shared between Drosophila oenocytes and mammalian liver, highlighting the molecular and functional similarities between the two tissues. Many of these genes are altered in both aged oenocytes and aged liver, suggesting a conserved molecular mechanism underlying oenocyte and liver aging. Thus, our translatome analysis will contribute significantly to the understanding of oenocyte biology, and its role in lipid metabolism, stress response and aging regulation.

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