scholarly journals Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Xin Xie ◽  
Yi-Fan Tie ◽  
Song Lai ◽  
Yun-Long Zhang ◽  
Hui-Hua Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Er Stress ◽  
Lipid Accumulation ◽  
Acid Metabolism ◽  
Heart Function ◽  
Underlying Mechanism ◽  
Immunofluorescent Staining ◽  
Proteomic Profiling ◽  
Cardiac Steatosis

AbstractExcess myocardial triacylglycerol accumulation (i.e., cardiac steatosis) impairs heart function, suggesting that enzymes promoting triacylglycerol metabolism exert essential regulatory effects on heart function. Comparative gene identification 58 (CGI-58) is a key enzyme that promotes the hydrolysis of triglycerides by activating adipose triglyceride lipase and plays a protective role in maintaining heart function. In this study, the effects of CGI-58 on heart function and the underlying mechanism were investigated using cardiac-specific CGI58-knockout mice (CGI-58cko mice). Echocardiography and pathological staining were performed to detect changes in the structure and function of the heart. Proteomic profiling, immunofluorescent staining, western blotting, and real-time PCR were used to evaluate molecular changes. In CGI-58cko mice, we detected cardiac hypertrophic remodeling and heart failure associated with excessive cardiac lipid accumulation, ROS production, and decreased expression of regulators of fatty acid metabolism. These changes were markedly attenuated in CGI-58cko mice injected with rAAV9-CGI58. A quantitative proteomics analysis revealed significant increases in the expression of ER stress-related proteins and decreases in proteins related to fatty acid and amino acid metabolism in the hearts of CGI-58cko mice. Furthermore, the inhibition of ER stress by the inhibitor 4-PBA improved mitochondrial dysfunction, reduced oxidative stress, and reversed cardiac remodeling and dysfunction in cultured cardiomyocytes or in CGI-58cko mice. Our results suggested that CGI-58 is essential for the maintenance of heart function by reducing lipid accumulation and ER stress in cardiomyocytes, providing a new therapeutic target for cardiac steatosis and dysfunction.

scholarly journals Aqueous Extract of Pepino Leaves Ameliorates Palmitic Acid-Induced Hepatocellular Lipotoxicity via Inhibition of Endoplasmic Reticulum Stress and Apoptosis

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 903
Author(s):  
Jen-Ying Hsu ◽  
Hui-Hsuan Lin ◽  
Charng-Cherng Chyau ◽  
Zhi-Hong Wang ◽  
Jing-Hsien Chen
Keyword(s):  
Fatty Acid ◽  
Palmitic Acid ◽  
Er Stress ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Liver Lipid ◽  
Antioxidant Response ◽  
Long Chain Fatty Acid ◽  
Nrf2 Expression

Saturated fatty acid is one of the important nutrients, but contributes to lipotoxicity in the liver, causing hepatic steatosis. Aqueous pepino leaf extract (AEPL) in the previous study revealed alleviated liver lipid accumulation in metabolic syndrome mice. The study aimed to investigate the mechanism of AEPL on saturated long-chain fatty acid-induced lipotoxicity in HepG2 cells. Moreover, the phytochemical composition of AEPL was identified in the present study. HepG2 cells treated with palmitic acid (PA) were used for exploring the effect of AEPL on lipid accumulation, apoptosis, ER stress, and antioxidant response. The chemical composition of AEPL was analyzed by HPLC-ESI-MS/MS. AEPL treatment reduced PA-induced ROS production and lipid accumulation. Further molecular results revealed that AEPL restored cytochrome c in mitochondria and decreased caspase 3 activity to cease apoptosis. In addition, AEPL in PA-stressed HepG2 cells significantly reduced the ER stress and suppressed SREBP-1 activation for decreasing lipogenesis. For defending PA-induced oxidative stress, AEPL promoted Nrf2 expression and its target genes, SOD1 and GPX3, expressions. The present study suggested that AEPL protected from PA-induced lipotoxicity through reducing ER stress, increasing antioxidant ability, and inhibiting apoptosis. The efficacy of AEPL on lipotoxicity was probably concerned with kaempferol and isorhamnetin derived compounds.

scholarly journals Delta-6-desaturase Links Polyunsaturated Fatty Acid Metabolism With Phospholipid Remodeling and Disease Progression in Heart Failure

2014 ◽  
Vol 7 (1) ◽  
pp. 172-183 ◽  
Author(s):  
Catherine H. Le ◽  
Christopher M. Mulligan ◽  
Melissa A. Routh ◽  
Gerrit J. Bouma ◽  
Melinda A. Frye ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Disease Progression ◽  
Polyunsaturated Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Delta 6 Desaturase

scholarly journals Diosgenin ameliorates palmitic acid-induced lipid accumulation via AMPK/ACC/CPT-1A and SREBP-1c/FAS signaling pathways in LO2 cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ke Fang ◽  
Fan Wu ◽  
Guang Chen ◽  
Hui Dong ◽  
Jingbin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Palmitic Acid ◽  
Mitochondrial Function ◽  
Lipid Accumulation ◽  
Lipid Synthesis ◽  
Underlying Mechanism ◽  
Intracellular Lipid

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is characterized by excessive hepatic lipid accumulation. Many studies have suggested that lipid overload is the key initial factor that contributes to hepatic steatosis. Our previous study indicated that diosgenin (DSG) has a beneficial effect on energy metabolism, but the underlying mechanism remains unclear. Methods Human normal hepatocytes (LO2 cells) were incubated with palmitic acid to establish the cell model of nonalcoholic fatty liver. The effects of DSG on lipid metabolism, glucose uptake and mitochondrial function were evaluated. Furthermore, the mechanism of DSG on oxidative stress, lipid consumption and lipid synthesis in LO2 cells was investigated. Results The results indicated that palmitic acid induced obvious lipid accumulation in LO2 cells and that DSG treatment significantly reduced the intracellular lipid content. DSG treatment upregulated expression of lipolysis proteins, including phospho-AMP activated protein kinase (p-AMPK), phospho-acetyl-coA carboxylase (p-ACC) and carnitine acyl transferase 1A (CPT-1A), and inhibited expression of lipid synthesis-related proteins, including sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS). Additionally, DSG-treated cells displayed a marked improvement in mitochondrial function, with less production of reactive oxygen species and a higher mitochondrial membrane potential compared with the model group. Conclusion This study suggests that DSG can reduce intracellular lipid accumulation in LO2 cells and that the underlying mechanism may be related to the improving oxidative stress, increasing fatty acid β-oxidation and decreasing lipid synthesis. The above changes might be mediated by the activation of the AMPK/ACC/CPT-1A pathway and inhibition of the SREBP-1c/FAS pathway.

Disorder of fatty acid metabolism in the kidney of PAN-induced nephrotic rats

2012 ◽  
Vol 303 (7) ◽  
pp. F1070-F1079 ◽  
Author(s):  
Yoshikazu Muroya ◽  
Osamu Ito ◽  
Rong Rong ◽  
Kenta Takashima ◽  
Daisuke Ito ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Lipid Accumulation ◽  
Acid Metabolism ◽  
Kidney Cortex ◽  
Tubular Damage ◽  
Sprague Dawley ◽  
Puromycin Aminonucleoside ◽  
Fatty Acid Binding ◽  
Tubulointerstitial Damage

Proteinuria is considered to play an essential role in the progression of tubulointerstitial damage, which causes end-stage renal disease. Fatty acid-binding albumins are filtered through glomeruli and reabsorbed into proximal tubular epithelial cells (PTECs). However, the role of fatty acid metabolism associated with albuminuria in the development of tubulointerstitial damage remains unclear. Thus, the present study was designed to determine the changes of fatty acid metabolism in the nephrotic kidney. To induce nephrotic syndrome, Sprague-Dawley rats (SDRs) and Nagase analbuminemic rats (NARs) with inherited hypoalbuminemia were treated with a single injection of puromycin aminonucleoside (PAN). In SDRs, PAN treatment induced massive proteinuria and albuminuria and caused tubular damage, apoptosis, and lipid accumulation in PTECs. Among the enzymes of fatty acid metabolism, expressions of medium-chain acyl-CoA dehydrogenase (MCAD) and cytochrome P-450 (CYP)4A significantly decreased in PTECs of PAN-treated SDRs. Expressions of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α and estrogen-related receptor (ERR)α also significantly decreased, without changes in the expression of PPAR-α. In NARs, PAN treatment induced proteinuria but not albuminuria and did not cause tubular damage, apoptosis, or lipid accumulation. Expressions of MCAD, PGC-1α, or ERRα did not change in the kidney cortex of PAN-treated NARs, but the expression of CYP4A significantly decreased. These results indicate that massive albuminuria causes tubular damage and lipid accumulation with the reduction of MCAD, CYP4A, PGC-1α, and ERRα in PTECs.

scholarly journals Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure

2016 ◽  
Vol 311 (4) ◽  
pp. H871-H880 ◽  
Author(s):  
Shun-Guang Wei ◽  
Yang Yu ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renin Angiotensin System ◽  
Mapk Signaling ◽  
Immunofluorescent Staining ◽  
Mrna Levels ◽  
Angiotensin System ◽  
System Activity ◽  
Renin Angiotensin

We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

scholarly journals MicroRNA 379 Regulates Klotho Deficiency–Induced Cardiomyocyte Apoptosis Via Repression of Smurf1

Hypertension ◽  
2021 ◽  
Author(s):  
Kai Chen ◽  
Bo Zhang ◽  
Zhongjie Sun
Keyword(s):  
Heart Failure ◽  
Apoptotic Cell ◽  
Heart Function ◽  
Underlying Mechanism ◽  
Cardiomyocyte Apoptosis ◽  
H9c2 Cell ◽  
Heart Cells ◽  
Sequencing Analysis ◽  
H9c2 Cells ◽  
Induced Apoptosis

Klotho is an aging-suppressor gene. Klotho gene deficiency impairs heart function leading to heart failure, but the underlying mechanism remains poorly understood. MicroRNAs are increasingly recognized to play important roles in the pathogenesis of cardiomyopathy. The objective of this study is to investigate whether microRNA 379 (Mir379) regulates Klotho deficiency-associated cardiomyocyte apoptosis. Using inducible Cre-Loxp recombination technology, we first found that kidney-specific deletion of the Klotho gene caused heart failure. Using microRNA sequencing analysis, we found that Mir379 may be a target of Klotho. In cultured H9c2 heart cells, we found that treatment with Klotho-free medium increased Mir379 levels and induced apoptosis. To test whether Mir379 mediates Klotho deficiency–induced apoptosis, H9c2 cells were transfected with Mir379 inhibitor. Interestingly, Mir379 inhibitor (anti-Mir379) prevented Klotho deficiency–induced H9c2 cell apoptosis. On the contrary, Mir379 mimic itself caused apoptosis in H9c2 cells. These findings suggest that Mir379 may mediate Klotho deficiency–induced apoptosis in H9C2 cells. Using the mRNA-miRNA target interaction assay, we found that Smurf1(SMAD specific E3 ubiquitin protein ligase 1) mRNA contained the 3-UTR binding site for Mir379. Importantly, Mir379 mimic suppressed Smurf1 expression, and the Mir379 mimic–induced apoptosis can be rescued by treatment with exogenous Smurf1 protein. Therefore, Smurf1 repression may be involved in Mir379–induced H9c2 cells apoptosis. In conclusion, Mir379 may mediate Klotho deficiency-associated cardiomyocyte apoptosis through repression of Smurf1 which is required for Mir379-induced apoptotic cell death. Mir379 may be a potential therapeutic target for cardiomyocyte apoptosis-associated heart failure due to Klotho deficiency.

scholarly journals Exploration the mechanism of doxorubicin-induced Heart failure in Rats by integration of proteomics and metabolomics data

2020 ◽  
Author(s):  
Yu Yuan ◽  
Simiao Fan ◽  
Lexin Shu ◽  
Wei Huang ◽  
Lijuan Xie ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Systemic Disease ◽  
Cardiac Metabolism ◽  
Glutathione Metabolism ◽  
High Morbidity ◽  
Metabolomics Data

Abstract Background Heart failure is currently a worldwide systemic disease with high morbidity and mortality and is very common. At present, many studies have shown that heart failure is associated with obesity, hypertension and diabetes, but it is still unable to prevent the disease from progressing. Here, we elucidate the molecular mechanisms of doxorubicin–induced harmful effects on rat cardiac metabolism and function from a new perspective, using metabonomics and Proteomics analysis data. Methods The aim of this study was to use metabonomic and proteomic techniques to systematically elucidate the molecular mechanisms of doxorubicin (DOX)–induced heart failure (HF) in rat. In this study, we aimed to systematically elucidate the molecular action of Dox on rats heart and the reasons for DOX–induced the HF mechanism through the metabonomics tandem mass tag (TMT)–based quantitative proteomics approach. Rats were gavaged with DOX (3 mg/kg) for 6 weeks and the plasma metabonomics, cardiac tissue proteomics, histopathology and related proteins expression levels. Results A total of 278 proteins and 21 metabolites were significantly altered in rats following DOX treatments. The responsive proteins and metabolites were predominantly involved in Fatty acid metabolism, Glycolysis, glycerophospholipid metabolism, TCA cycle, Glutathione metabolism, Myocardial contraction. Conclusions The present study indicates the PTP1B inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc and AK4 proteins lead to oxidative stress, suggesting the PTP1B may serve as a potential target in the treatment of heart failure.

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