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The Potential of ANGPTL8 Antagonism to Simultaneously Reduce Triglyceride and Increase HDL-Cholesterol Plasma Levels.

ABSTRACT: Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease. Therefore, a drug that simultaneously reduces TG and increases HDL-C plasma levels has the potential to prevent and treat these diseases. Angiopoietin-like 3 (ANGPTL3) regulates plasma TG and HDL-C levels by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), respectively. ANGPTL3 inhibition of LPL requires complex formation with ANGPTL8, which is not required for its inhibition of EL. Therefore, the entire pool of plasma ANGPTL3 can be classified as ANGPTL8-associated ANGPTL3 and ANGPTL8-free ANGPTL3, where the former inhibits LPL and the latter inhibits EL. ANGPTL8 antibodies or inhibitors that block its interactions with ANGPTL3 can disrupt or preclude the ANGPTL3-8 complex formation, resulting in fewer ANGPTL3-8 complexes (reduced LPL inhibition), but more free ANGPTL3 (enhanced EL inhibition). Therefore, ANGPTL8 antagonism increases LPL activity while decreasing EL activity, thus leading to reduced plasma TG while simultaneously increasing HDL-C levels. In humans, carriers of ANGPTL8 truncating variants consistently have lower TG but higher HDL-C levels, supporting this hypothesis.

SUBMITTER: Zhang R

PROVIDER: S-EPMC8635044 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study aims to evaluate levels of D-dimer and serum lipid in different types of pancreatitis, and the relationship between D-dimer and dyslipidemia, especially triglyceride to HDL-C ratio (TG/HDL-C) in different types of pancreatitis. We analyzed the D-dimer and dyslipidemia levels in acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). A single-centered retrospective study was conducted on 1013 patients diagnosed with AP, RAP or CP. Only patients hospitalized within 24 h of onset were included, and 204 patients were enrolled in pancreatitis groups. 68 normal persons without pancreatitis, malignant diseases, pregnancy, or organ failure, who had health check-ups, were enrolled in the control group. Blood samples were taken within 24 h of admission. The relevant information on epidemiology and etiology was collected. D-dimer and serum lipid levels in different types of pancreatitis were analyzed. Furthermore, the area under the receiver-operating characteristic curve (AUC) was used to estimate the validity of the predictor and to define optimal cut-off points for prediction. We found that D-dimer and TG/HDL-C ratio could distinguish mild AP (MAP) and non-MAP in AP and RAP patients. The D-dimer level was related to TG/HDL-C ratio and severity of pancreatitis, with the coefficient correlation of 0.379 and 0.427(p < 0.05), respectively. TG/HDL-C was related to D-dimer in different types of pancreatitis. Logistic regression analysis was conducted in the parameters at admission like alcohol abuse, dyslipidemia and coagulation disturbance in distinguishing AP and RAP groups from the control group, and the parameter like diabetes in RAP and CP groups significantly increased compared with that of the control group. The value of D-dimer level and TG/HDL-C ratio in predicting the severity of AP and RAP was confirmed but there was no significant difference between CP group and the control group. The D-dimer level was related to dyslipidemia and TG/HDL-C ratio.

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The Potential of ANGPTL8 Antagonism to Simultaneously Reduce Triglyceride and Increase HDL-Cholesterol Plasma Levels.

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