Abstract 203: Role of Glucagon Receptor Signalling in PCSK9 Regulation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Stefano Spolitu ◽  
Lale Ozcan
Keyword(s):  
Lipid Metabolism ◽  
Blood Glucose ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Receptor Protein ◽  
Obese Mice ◽  
Glucagon Receptor ◽  
Protein Levels ◽  
New Findings

Excessive glucagon receptor action in hepatocytes is a major contributing factor to type 2 diabetes (T2D). Accordingly, there has been great interest in developing glucagon receptor antagonists (GRAs) as a treatment for T2D. Although phase 2 clinical trials have shown that GRAs effectively lower blood glucose in T2D subjects, they increase plasma low density lipoprotein (LDL) cholesterol levels, which has presented a significant block to their development. In this context, recent studies have suggested that cholesterol and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels can be regulated by fasting and perhaps glucagon, but in-depth mechanistic insight is lacking. In order to test the functional importance of hepatic glucagon action on lipid metabolism, we silenced glucagon receptor (GcgR) in obese mice using AAV8-H1-shGcgr to silence the receptor in hepatocytes. Consistent with previous reports, this treatment effectively lowered blood glucose in obese mice without a change in body weight. Moreover, GcgR silencing, like GRAs in humans, significantly increased plasma LDL cholesterol. In search for the mechanism, we found that inhibition of GcgR significantly lowered hepatic LDL-receptor protein levels and increased both hepatic PCSK9 and circulating PCSK9. To determine causation, we treated GcgR-silenced mice with a neutralizing monoclonal antibody against PCSK9 and found that this intervention restored hepatic LDL-receptor protein levels and prevented the increase in LDL cholesterol. Further mechanistic work revealed that GcgR silencing in hepatocytes did not increase Pcsk9 mRNA. Rather, blocking GcgR increased the half-life of PCSK9 protein by suppressing signalling through exchange protein activated by cAMP 1 (Epac1). In particular, the ability of GcgR silencing to increase PCSK9 and suppress LDL receptor protein levels was mimicked by hepatocytes lacking Epac1. Thus, GcgR signalling through Epac1 appears to have critical effects on processes that regulate cholesterol metabolism through PCSK9. These new findings have important implications for the lipid metabolism effects of hepatic glucagon signalling in both normal physiology and metabolic disease, and for the development of safer GRA-like drugs to treat T2D.

scholarly journals FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

2018 ◽  
Vol 59 (6) ◽  
pp. 982-993 ◽  
Author(s):  
Romeo Papazyan ◽  
Xueqing Liu ◽  
Jingwen Liu ◽  
Bin Dong ◽  
Emily M. Plummer ◽  
...  
Keyword(s):  
Target Gene ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Receptor Protein ◽  
Chimeric Mice ◽  
Obeticholic Acid ◽  
Protein Levels ◽  
Mechanistic Basis

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

scholarly journals Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels are not associated with severity of liver disease and are inversely related to cholesterol in a cohort of thirty eight patients with liver cirrhosis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Susanne Feder ◽  
Reiner Wiest ◽  
Thomas S. Weiss ◽  
Charalampos Aslanidis ◽  
Doris Schacherer ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Cholesteryl Ester ◽  
Hepatic Vein ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Receptor Protein ◽  
Proprotein Convertase ◽  
Protein Levels ◽  
Systemic Vein

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of particular importance in cholesterol metabolism with high levels contributing to hypercholesterolemia. Cholesterol and sphingolipids are low in patients with liver cirrhosis. Purpose of this study was to find associations of plasma PCSK9 with circulating cholesterol and sphingolipid species and measures of liver disease severity in patients with liver cirrhosis. Methods PCSK9 protein levels were determined by ELISA in systemic vein (SVP), hepatic vein (HVP) and portal vein plasma of patients with mostly alcoholic liver cirrhosis. PCSK9 and LDL-receptor protein expression were analysed in cirrhotic and non-cirrhotic liver tissues. Results Serum PCSK9 was reduced in patients with liver cirrhosis in comparison to non-cirrhotic patients. In liver cirrhosis, plasma PCSK9 was not correlated with Child-Pugh score, Model for End-Stage Liver Disease score, bilirubin or aminotransferases. A negative association of SVP PCSK9 with albumin existed. PCSK9 protein in the liver did not change with fibrosis stage and was even positively correlated with LDL-receptor protein levels. Ascites volume and variceal size were not related to PCSK9 levels. Along the same line, transjugular intrahepatic shunt to lower portal pressure did not affect PCSK9 concentrations in the three blood compartments. Serum cholesterol, sphingomyelin and ceramide levels did not correlate with PCSK9. Stratifying patients by high versus low PCSK9 levels using the median as cut-off, several cholesteryl ester species were even low in the subgroup with high PCSK9 levels. A few sphingomyelin species were also reduced in the patients with PCSK9 levels above the median. PCSK9 is highly expressed in the liver but systemic, portal and hepatic vein levels were similar. PCSK9 was not correlated with the inflammatory proteins C-reactive protein, IL-6, galectin-3, resistin or pentraxin 3. Of note, HVP PCSK9 was positively associated with HVP chemerin and negatively with HVP adiponectin levels. Conclusions In the cohort of patients with liver cirrhosis mostly secondary to alcohol consumption high PCSK9 was associated with low levels of certain cholesteryl ester and sphingomyelin species. Positive correlations of PCSK9 and LDL-receptor protein in the liver of patients with chronic liver injury are consistent with these findings.

scholarly journals AMPK subunits harbor largely non-overlapping genetic determinants for body fat mass, glucose- and cholesterol metabolism

2019 ◽  
Author(s):  
Elko Randrianarisoa ◽  
Angela Lehn-Stefan ◽  
Johannes Krier ◽  
Anja Böhm ◽  
Martin Heni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Hdl Cholesterol ◽  
Oral Glucose ◽  
Genetic Determinants ◽  
The Impact

Abstract Context AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all seven subunit genes on adiposity, glucose- and lipid metabolism has not been systematically studied yet. Objective To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-, LDL- and HDL-cholesterol and triglycerides. Study Design and Methods A cohort of 2789 non-diabetic subjects from the Tübingen Family study of type-2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array was analyzed. Results We identified largely non-overlapping SNP sets across four AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-/LDL-cholesterol or HDL-cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on BMI of +0.22 kg/m² (p=2.3·10-7), insulin sensitivity of -0.12·1019 L²/mol² (p=9.9·10-6) and 2-h blood glucose of +0.02 mmol/L (p=0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total- and LDL-cholesterol by 1.17 mg/dL per allele (p=0.0002 and p=3.2·10-5, respectively), and a genetic HDL score decreased HDL-cholesterol by 0.32 mg/dL per allele (p=9.1·10-6). Conclusions We describe largely non-overlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size.

Chromium Yeast Supplementation Improves Fasting Plasma Glucose and LDL-Cholesterol in Streptozotocin-Induced Diabetic Rats

2006 ◽  
Vol 76 (6) ◽  
pp. 391-397 ◽  
Author(s):  
Lai ◽  
Chen ◽  
Cheng
Keyword(s):  
Lipid Metabolism ◽  
Blood Glucose ◽  
Body Mass ◽  
Ldl Cholesterol ◽  
Fasting Blood Glucose ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Diabetic Rats ◽  
Significant Difference ◽  
Chromium Yeast

Chromium yeast supplementation has been studied for its ability to improve carbohydrate and lipid abnormalities. There have been some earlier literature-reported studies involving chromium supplementation amongst patients suffering diabetes, but the results would appear to be somewhat varied. Forty male Wistar rats (ten weeks old, 300 g in average body mass) were divided into one of four groups, namely (i) controls; (ii) controls treated with chromium yeast; (iii) diabetic controls; and (iv) diabetic rats treated with chromium yeast. In the present investigation, the effect of a four-week oral administration of chromium yeast (600 μg of Cr/kg body mass/day, by gavage) upon the glucose and lipid metabolism in streptozotocin (STZ)-induced diabetic rats was assessed. Supplemental Cr yeast decreased the fasting blood glucose amongst the STZ-diabetic rats. No significant difference was observed in plasma fructosamine levels of rats treated with chromium yeast compared to control rats. Supplemental Cr yeast did decrease the plasma low-density lipoprotein (LDL)-cholesterol level for the STZ-diabetic rats as compared to controls. We noted no significant effect of chromium supplementation upon plasma high-density lipoprotein (HDL)-cholesterol or triglycerides compared to controls. Treatment with chromium yeast significantly increased the blood and urine chromium levels for both the diabetic and normal rats compared to respective control groups. The results of these studies suggest that Cr yeast decreased the fasting blood glucose and LDL-cholesterol levels in STZ-induced diabetic rats. This raises the possibility that Cr yeast supplementation can be considered to improve carbohydrate and lipid metabolism amongst human patients featuring type 2 diabetes mellitus.

scholarly journals Ginkgolide B Mediated Alleviation of Inflammatory Cascades and Altered Lipid Metabolism in HUVECs via Targeting PCSK-9 Expression and Functionality

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Gang Wang ◽  
Zhenbin Liu ◽  
Menghu Li ◽  
Yu Li ◽  
Sahir Sultan Alvi ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Adhesion Molecule ◽  
Protein Level ◽  
In Silico ◽  
Cholesterol Metabolism ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Ginkgolide B ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1β, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.

scholarly journals Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Elisabeth M. Haberl ◽  
Rebekka Pohl ◽  
Lisa Rein-Fischboeck ◽  
Marcus Höring ◽  
Sabrina Krautbauer ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
Hepatic Lipase ◽  
Ldl Receptor ◽  
Experimental Models ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Paired Student ◽  
Normal Chow

Abstract Background Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed. Methods Lipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis. Results Intra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors. Conclusions Ceramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.

scholarly journals Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

2021 ◽  
Vol 22 (10) ◽  
pp. 5297
Author(s):  
Elisabeth M. Haberl ◽  
Thomas S. Weiss ◽  
Georg Peschel ◽  
Kilian Weigand ◽  
Nikolai Köhler ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Metabolism ◽  
Hepatitis B ◽  
Free Cholesterol ◽  
Cholesterol Metabolism ◽  
P53 Protein ◽  
Tumor Grade ◽  
Chronic Viral Hepatitis ◽  
Disease Etiology ◽  
Protein Levels

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.

scholarly journals Sesamol Alleviates Obesity-Related Hepatic Steatosis via Activating Hepatic PKA Pathway

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 329 ◽  
Author(s):  
Hai-Yan Xu ◽  
Liang Yu ◽  
Ji-Hua Chen ◽  
Li-Na Yang ◽  
Cui Lin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Protein Kinase ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
The Body ◽  
Obese Mice ◽  
Protein Levels ◽  
Pka Pathway

This study aimed to investigate the effect of sesamol (SEM) on the protein kinase A (PKA) pathway in obesity-related hepatic steatosis treatment by using high-fat diet (HFD)-induced obese mice and a palmitic acid (PA)-treated HepG2 cell line. SEM reduced the body weight gain of obese mice and alleviated related metabolic disorders such as insulin resistance, hyperlipidemia, and systemic inflammation. Furthermore, lipid accumulation in the liver and HepG2 cells was reduced by SEM. SEM downregulated the gene and protein levels of lipogenic regulator factors, and upregulated the gene and protein levels of the regulator factors responsible for lipolysis and fatty acid β-oxidation. Meanwhile, SEM activated AMP-activated protein kinase (AMPK), which might explain the regulatory effect of SEM on fatty acid β-oxidation and lipogenesis. Additionally, the PKA-C and phospho-PKA substrate levels were higher after SEM treatment. Further research found that after pretreatment with the PKA inhibitor, H89, lipid accumulation was increased even with SEM administration in HepG2 cells, and the effect of SEM on lipid metabolism-related regulator factors was abolished by H89. In conclusion, SEM has a positive therapeutic effect on obesity and obesity-related hepatic steatosis by regulating the hepatic lipid metabolism mediated by the PKA pathway.

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