Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

2018 ◽  
Vol 38 (3) ◽  
pp. 356-370 ◽  
Author(s):  
A Gautam ◽  
YN Paudel ◽  
SAZ Abidin ◽  
U Bhandari
Keyword(s):  
Hepatic Injury ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Farnesoid X Receptor ◽  
Lipoprotein Cholesterol ◽  
In Vivo Studies ◽  
Low Density Lipoprotein Cholesterol ◽  
Pro Inflammatory Cytokines

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine- N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC–MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.

scholarly journals Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xinxin Zhang ◽  
Yating Qin ◽  
Xiaoning Wan ◽  
Hao Liu ◽  
Chao Iv ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Fold Increase ◽  
Heart Tissue ◽  
Control Group ◽  
Atherosclerotic Lesions ◽  
Serum Crp

Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods. Male apoE-/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE-/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

scholarly journals Effects of retinoid therapy on insulin sensitivity, lipid profile and circulating adipocytokines

2006 ◽  
Vol 154 (1) ◽  
pp. 83-86 ◽  
Author(s):  
S Corbetta ◽  
R Angioni ◽  
A Cattaneo ◽  
P Beck-Peccoz ◽  
A Spada
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Lipid Profile ◽  
Oral Treatment ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Glucose And Lipid Metabolism ◽  
Cholesterol Levels

Objective: In vitro and in vivo models indicate that all-trans retinoic acids influence glucose and lipid metabolism. We aimed to evaluate the effects of chronic treatment with acitretin, an all-trans retinoic acid, on glucose metabolism, lipid profile and adiponectin and resistin levels. Design: Ten normoglycemic, normolipemic patients affected with psoriasis vulgaris were studied before and after 1 and 3 months of oral treatment with 35 μg of acitretin. Methods: Glucose metabolism, lipid profile, and adiponectin and resistin levels were evaluated in basal conditions and after acitretin treatment. Ten healthy subjects matched for age, body mass index (BMI) and insulin sensitivity were studied as controls. Results: One-month acitretin treatment reduced psoriasis activity, insulin sensitivity, evaluated as QUICKI values (0.364 ± 0.034 versus 0.329 ± 0.051; P < 0.05) and HOMA-IR index (1.53 ± 0.73 versus 2.59 ± 1.41; P < 0.05), and high-density lipoprotein (HDL)-cholesterol levels (45.2 ± 11.7 versus 39.4 ± 10.4 mg/dl; P = 0.01). The impairment in glucose and lipid homeostasis was transient and not associated to BMI variations. Adiponectin levels did not change during the treatment, while resistin levels, which were higher in untreated patients than in controls (9.4 ± 4.4 versus 6.2 ± 2.1 ng/ml; P = 0.05), fell within the normal range after 1 and 3 months of therapy. The normalization of resistin levels occurred without significant changes in circulating tumor necrosis factor α (TNFα) levels, which persisted elevated throughout the treatment. Conclusions: Treatment with a low dose of acitretin induced a mild, transient reduction of insulin sensitivity and HDL-cholesterol levels that was not related to modifications of adiponectin, resistin and TNFα levels. Although the role of resistin in humans remains elusive, the levels of this adipocytokine seem to be affected, at least in part, by retinoids.

scholarly journals Adenovirus-Mediated High Expression of Resistin Causes Dyslipidemia in Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 273-279 ◽  
Author(s):  
Naoichi Sato ◽  
Kunihisa Kobayashi ◽  
Toyoshi Inoguchi ◽  
Noriyuki Sonoda ◽  
Minako Imamura ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Glucose Production ◽  
Low Density ◽  
Adenoviral Gene Transfer ◽  
Insulin Resistant

The adipocyte-derived hormone resistin has been proposed as a possible link between obesity and insulin resistance in murine models. Many recent studies have reported physiological roles for resistin in glucose homeostasis, one of which is enhancement of glucose production from the liver by up-regulating gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. However, its in vivo roles in lipid metabolism still remain to be clarified. In this study, we investigated the effects of resistin overexpression on insulin action and lipid metabolism in C57BL/6 mice using an adenoviral gene transfer technique. Elevated plasma resistin levels in mice treated with the resistin adenovirus (AdmRes) were confirmed by Western blotting analysis and RIAs. Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice. In AdmRes-treated mice, the glucose-lowering effect of insulin was impaired, as evaluated by insulin tolerance tests. Furthermore, total cholesterol and triglyceride concentrations were significantly higher, whereas the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice, compared with controls. In addition, in vivo Triton WR-1339 studies showed evidence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as low-density lipoprotein receptor and apolipoprotein AI in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is commonly seen in the insulin-resistant state, partially through enhanced secretion of lipoproteins.

scholarly journals The Molecular Mechanisms of Hypoglycemic Properties and Safety Profiles of Swietenia Macrophylla Seeds Extract: A Review

2021 ◽  
Vol 9 (F) ◽  
pp. 370-388
Author(s):  
Ratih Dewi Yudhani ◽  
Dwi Aris Agung Nugrahaningsih ◽  
Eti Nurwening Sholikhah ◽  
Mustofa Mustofa
Keyword(s):  
Oxidative Stress ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Density Lipoprotein ◽  
Thiobarbituric Acid ◽  
In Vitro Cytotoxicity ◽  
Swietenia Macrophylla

BACKGROUND: Insulin resistance (IR) is known as the root cause of type 2 diabetes; hence, it is a substantial therapeutic target. Nowadays, studies have shifted the focus to natural ingredients that have been utilized as a traditional diabetes treatment, including Swietenia macrophylla. Accumulating evidence supports the hypoglycemic activities of S. macrophylla seeds extract, although its molecular mechanisms have yet to be well-established. AIM: This review focuses on the hypoglycemic molecular mechanisms of S. macrophylla seeds extract and its safety profiles. METHODS: An extensive search of the latest literature was conducted from four main databases (PubMed, Scopus, Science Direct, and Google Scholar) using several keywords: “swietenia macrophylla, seeds, and diabetes;” “swietenia macrophylla, seeds, and oxidative stress;” “swietenia macrophylla, seeds, and inflammation;” “swietenia macrophylla, seeds, and GLUT4;” and “swietenia macrophylla, seeds, and toxicities.” RESULTS: The hypoglycemic activities occur through modulating several pathways associated with IR and T2D pathogenesis. The seeds extract of S. macrophylla modulates oxidative stress by decreasing malondialdehyde (MDA), oxidized low-density lipoprotein, and thiobarbituric acid-reactive substances while increasing antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase). Another propose mechanism is the modulating of the inflammatory pathway by attenuating nuclear factor kappa β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2. Some studies have shown that the extract can also control phosphatidylinositol-3-kinase/ Akt (PI3K/Akt) pathway by inducing glucose transporter 4, while suppressing phosphoenolpyruvate carboxykinase. Moreover, in vitro cytotoxicity and in vivo toxicity studies supported the safety profile of S. macrophylla seeds extract with the LD50 higher than 2000 mg/kg. CONCLUSION: The potential of S. macrophylla seeds as antidiabetic candidate is supported by many studies that have documented their non-toxic and hypoglycemic effects, which involve several molecular pathways.

Abstract 168: Effects of the CETP Inhibitor Anacetrapib on HDL3-to-HDL2 Transfer: Comparison of in Vitro and in Vivo Methodologies

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Douglas G Johns ◽  
Ying Chen ◽  
Erin D Daniels ◽  
Jose Castro-Perez ◽  
Sheng-Ping Wang ◽  
...  
Keyword(s):  
Lipoprotein Metabolism ◽  
Hdl Cholesterol ◽  
Transfer Protein ◽  
Cetp Inhibitor ◽  
Cetp Inhibition ◽  
Artery Disease ◽  
Maximal Reduction ◽  
Over Time

Cholesteryl ester transfer protein (CETP) is a target for the treatment of dyslipidemia and coronary artery disease. In addition to the well-known effect of CETP to transfer CE from HDL to LDL and to VLDL, in vitro , CETP has been reported to transfer CE between small and large HDL particles (HDL2 and HDL3, respectively). We sought to understand how the CETP inhibitor anacetrapib (ANA) affects HDL3-to-HDL2 transfer under both in vitro and in vivo conditions. In vitro , ANA dose-dependently inhibited transfer of 3 H-CE from total HDL to LDL (IC50 30nM), and from isolated HDL3 to HDL2 particles (IC50 200nM). In human CETP transgenic mice, animals treated with a single dose of ANA (100mg/kg) displayed 80% maximal reduction in plasma CETP activity and a 22% increase in total HDL cholesterol. In animals treated with either vehicle or ANA, 3 H-CE-labeled HDL3 was injected intravenously and 3 H-tracer was monitored in lipoprotein fractions following injection. Animals treated with ANA showed an increase in the amount 3 H-tracer present in HDL2 compared to vehicle over time (20-70% increase across 6 hrs post 3 H-CE-HDL3 injection, P<0.05 vs vehicle). The HDL2 CE pool was also increased with ANA treatment, and 3 H-cholesterol flux into HDL2 was increased with ANA treatment when adjusted to the change in pool size (at 2 and 4 hrs post 3H-CE-HDL3 injection). No change in HDL2 3 H-tracer was seen in C57BL6 mice (lacking CETP) treated with ANA. These results indicate that in contrast to in vitro findings, ANA increases flux of CE into HDL2 in vivo , a process which likely involves multiple pathways. Therefore, the in vitro phenomena of 1) HDL3-to-HDL2 transfer by CETP and 2) inhibition of this transfer by CETP inhibitors are not recapitulated in vivo . It is clear that in vivo approaches are necessary to understand the relevance of HDL3-to-HDL2 transfer in vivo , and to accurately study the effects of CETP inhibition on lipoprotein metabolism.

GH002: A Novel and Potent Agents for Elevating HDL-Cholesterol

2011 ◽  
Vol 340 ◽  
pp. 337-343
Author(s):  
Guo Lei
Keyword(s):  
Hepg2 Cells ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Control Group ◽  
Vitro Assay ◽  
Cholesterol Levels ◽  
Promoter Effects ◽  
Positive Effect

The aim of this study was to evaluate whether the positive effect of GH002 on high-density lipoprotein (HDL) cholesterol in vitro and in vivo. In vitro assay, effects of GH002 on apolipoprotein (apo) A-I was studied using stable-transfected HepG2 cells with recombinant vector including apoA-I promoter; Effects of GH002 on apoA-I, apoA-II and apoC-III production were determined using HepG2 cells. In vivo assay, Effects of GH002 on lipid profile were investigated in hyperlipidemic rats. The results showed that GH002 can effectively activate apoA-I promoter, enhance apoA-I and apoA-II secretion in vitro, whereas reduce apoC-III production significantly. Furthermore, after in vivo study that the hyperlipidemic rats were treated with GH002, HDL-cholesterol levels were increased significantly (P<0.01) at 2 weeks (100 mg/kg, 28.8%) and 3 weeks (30mg/kg, 19.8% and 100mg/kg, 36.4%, respectively) compared with control group. Triglyceride levels were reduced significantly at 2 and 3 weeks (19.5%, P<0.05 and 28.1%, P<0.01 respectively). Total cholesterol levels also were reduced at 3 weeks (19.1%, P<0.05) after 100mg/kg GH002 administration, but GH002 didn’t increase the ratio of liver/body weight compared with the control group at the end of the experiments. It is therefore reasonable to assume that GH002 is an effectively HDL-cholesterol enhancer by regulating apoA-I gene expression, consequently enhancing apoA-I, apoA-II secretion and reducing apoC-III production.

scholarly journals Endoplasmic Reticulum Stress Affects Lipid Metabolism in Atherosclerosis Via CHOP Activation and Over-Expression of miR-33

2018 ◽  
Vol 48 (5) ◽  
pp. 1995-2010 ◽  
Author(s):  
Yan Sun ◽  
Dai Zhang ◽  
Xiaoli Liu ◽  
Xuesong Li ◽  
Fang Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Er Stress ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Metabolism Disorder ◽  
Metabolism Disorder ◽  
The Relationship

Background/Aims: Endoplasmic reticulum (ER) stress is an important event in atherosclerosis. Recent studies have shown that ER stress deregulates cholesterol metabolism via multiple pathways. This study aimed to determine the relationship between ER stress and lipid metabolism and to verify that upregulation of miR-33 is involved in this process. Methods: An atherosclerosis model was established in apolipoprotein E-deficient (ApoE-/-) mice fed a Western diet, and THP-1 derived macrophages were used in this study. Hematoxylin-eosin and Oil Red O staining were used to quantify the atherosclerotic plaques. 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate labeled oxidized low-density lipoprotein binding assay and a Cholesterol Efflux Fluorometric Assay Kit were used to observe cholesterol uptake and efflux. The mRNA and protein levels of biomarkers associated with ER stress and cholesterol metabolism in atherosclerotic plaques and macrophages were evaluated by real-time PCR and western blotting, respectively. Immunofluorescence was used to observe alterations of ABCA1 localization. Small interfering RNAs were used to knock down CHOP and miR-33 in macrophages to alter CHOP and miR-33 expression. Results: Atherosclerotic lesions and systemic lipid levels were ameliorated after inhibition of ER stress (tauroursodeoxycholic acid) in vivo. In vitro studies confirmed that ER stress regulated the lipid catabolism of macrophages by promoting cholesterol uptake, inhibiting cholesterol efflux, and modulating the expression of related transporters. CHOP contributed to lipid metabolism disorder following ER stress. Furthermore, over-expression of miR-33 was involved in ER stress that induced lipid metabolism disorder in macrophages. These findings support a model of ER stress induction by oxidized low-density lipoprotein that affects macrophage lipid catabolism disorder. Conclusion: Our data shed new light on the relationship between ER stress and lipid metabolism in vivo and in vitro, and confirm that upregulation of miR-33 is involved in this process. The relationship between ER stress and miR-33 represents a novel target for the treatment of atherosclerosis.

scholarly journals Punicalagin Attenuates Disturbed Flow-Induced Vascular Dysfunction by Inhibiting Force-Specific Activation of Smad1/5

2021 ◽  
Vol 9 ◽  
Author(s):  
Gulinigaer Anwaier ◽  
Guan Lian ◽  
Gui-Zhi Ma ◽  
Wan-Li Shen ◽  
Chih-I Lee ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Protective Effects ◽  
Disturbed Flow ◽  
Atherosclerosis Progression

BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.

Galectin-3 Mediates Cardiac Remodeling Caused by Impaired Glucose and Lipid Metabolism Through Inhibiting Two Pathways of Activating Akt

2020 ◽  
Author(s):  
Zhen Sun ◽  
Lili Zhang ◽  
Lihua Li ◽  
Chen Shao ◽  
Jia Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Cardiac Remodeling ◽  
Density Lipoprotein ◽  
Myocardial Damage ◽  
Diabetic Patients ◽  
Glucose And Lipid Metabolism ◽  
Lipid Metabolism Disorders ◽  
Galectin 3

Pathological cardiac remodeling is a leading cause of mortality in diabetic patients. Given the glucose and lipid metabolism disorders (GLD) in diabetic patients, it is urgent to conduct a comprehensive study of the myocardial damage under GLD and find key mechanisms. Apolipoprotein E knockout (ApoE-/-) mice, low-density lipoprotein receptor heterozygote (Ldlr+/-) syrian golden hamsters or H9C2 cells were used to construct GLD models -. And GLD significantly promoted cardiomyocyte fibrosis, apoptosis and hypertrophy in vivo and in vitro, while inhibition of galectin-3 (Gal-3) could significantly reverse this process. Then, the signal transmission pathways were determined. It was found that GLD considerably inhibited the phosphorylation of Akt at Thr308 / Ser473, whereas the silencing of Gal-3 could reverse the inhibition of Akt activity through PI3K-AktThr308 and AMPK-mTOR2-AktSer473 pathways. Finally, the PI3K, mTOR, AMPK inhibitor and Akt activator were used to investigate the role of pathways in regulating cardiac remodeling. Phospho-AktThr308 could mediate myocardial fibrosis, while myocardial apoptosis and hypertrophy were regulated by both phospho-AktThr308 and phospho-AktSer473. In conclusion, Gal-3 was an important regulatory factor in GLD-induced cardiac remodeling, and Gal-3 could suppress the phosphorylation of Akt at different sites in mediating cardiomyocyte fibrosis, apoptosis and hypertrophy.

Sign in / Sign up

Export Citation Format

Share Document