Apolipoprotein CIII and diabetes. Is there a link?

Christopoulou, Eliza; Tsimihodimos, V.; Filippatos, Theodosios D.; Elisaf, Moses

doi:10.1002/dmrr.3118

Cited by 17 publications

(15 citation statements)

References 105 publications

(256 reference statements)

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“…Apolipoprotein C3 (APOC3) is a small protein on the surface of lipoprotein particles and has a vital role in regulating triglyceride metabolism. APOC3 has a potent inhibitor effect on lipoprotein lipase [ 106 ]. A study by Pavia et al indicated that overexpression of APOC3 results in pathological features in the liver similar to NAFLD such as inflammation, hepatocyte apoptosis, oxidative stress, and increased liver lipid content [ 107 ].…”

Section: Discussionmentioning

confidence: 99%

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Mahmoudi

Butler

Jamialahmadi

et al. 2021

BioMed Research International

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Background. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. Methods. We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. Results. We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Conclusion. Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Mahmoudi

Butler

Jamialahmadi

et al. 2021

BioMed Research International

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“…Even after additional adjustment for baseline hs-CRP, blood glucose and other risk factors, the results were unchangeable. The mediation of triglycerides may be explained by the ability of apoC-III to increase triglyceride levels by delaying and preventing the clearance of triglyceride-rich lipoproteins 7 and promoting very-low-density lipoprotein assembly and secretion, 21 which is the critical role of apoC-III in modulating glucose metabolism. Genetic studies of APOC3 loss-of-function variants, showing the association with lower levels of triglycerides and a reduced risk of cardiovascular disease, 22 23 supported our findings.…”

Section: Discussionmentioning

confidence: 99%

“…Previous experimental studies suggested that apolipoprotein Cs (apoCs), especially apoC-II and apoC-III, as the components of triglyceride-rich lipoproteins, have a great influence on the lipolysis of triglycerides, 5 as well as the ability to regulate insulin signalling, pancreatic beta-cell apoptosis and inflammation. [6][7][8] These studies provided pathophysiological evidence for the…”

Section: Introductionmentioning

confidence: 86%

Association of apolipoprotein Cs with new-onset type 2 diabetes mellitus: findings from the Chinese multi-provincial cohort study

Zhao

Liu

et al. 2021

BMJ Open

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ObjectivesApolipoprotein Cs (apoCs), especially apoC-II and apoC-III, as the components of triglyceride-rich lipoproteins, play a key role in the pathophysiology of diabetes. However, prospective studies examining direct associations between apoCs and diabetes are not reproducible. The aim of this study was to evaluate the impact of apoCs on the risk of developing diabetes in a middle-aged population, and to explore possible mediators responsible for the relationship between apoCs and diabetes.DesignProspective cohort study.SettingCommunity-based study carried out in Beijing.MethodsApoCs were measured in 1085 participants aged 45–74 years and free of type 2 diabetes mellitus (T2DM) at baseline from the Chinese Multi-Provincial Cohort Study-Beijing Project. Multivariate logistic regression was performed to examine the association of apoCs with a 5-year risk of new-onset T2DM. The impacts of triglycerides, insulin and high-sensitivity C reactive protein (hs-CRP) on the association between apoC-III and the risk of T2DM were explored by a mediation test.ResultsDuring the 5 years of follow-up, 97 (8.9%) participants developed T2DM. ApoC-III was significantly associated with the risk of developing T2DM after multivariable adjustment (OR=1.40; 95% CI 1.07 to 1.82). This association was mainly mediated by triglyceride levels with a significant indirect effect (OR 1.61; 95% CI 1.19 to 2.18), followed by hs-CRP and insulin.ConclusionsOur findings demonstrated that higher serum apoC-III was independently associated with increased 5-year risk of new-onset T2DM in the Chinese population, and triglyceride plays a crucial role in mediating this relationship. More attention should be paid to preventive strategies of T2DM targeting apoC-III.

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“…In addition to that, the inhibition of Apo C-III expression by insulin is important in regulating the serum concentration of APO C-III-rich lipoproteins, including chylomicrons and VLDL. In states of insulin resistance and diabetes mellitus, Apo CIII levels will increase [ 120 ]. APO C-III inhibits cellular uptake of TG-rich lipids and is a known inhibitor of lipoprotein lipase (LPL), resulting in delayed clearance of TG-rich lipoproteins from circulation [ 121 ].…”

Section: Dyslipidemia In Type 2 Diabetes Mellitusmentioning

confidence: 99%

Diabetes Mellitus and Its Metabolic Complications: The Role of Adipose Tissues

Dilworth

Facey

Omoruyi

2021

IJMS

155

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Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.

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Apolipoprotein CIII and diabetes. Is there a link?

Cited by 17 publications

References 105 publications

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Association of apolipoprotein Cs with new-onset type 2 diabetes mellitus: findings from the Chinese multi-provincial cohort study

Diabetes Mellitus and Its Metabolic Complications: The Role of Adipose Tissues

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