Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Abstract

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Mapping the sites of the lipoprotein lipase (LPL)–angiopoietin-like protein 4 (ANGPTL4) interaction provides mechanistic insight into LPL inhibition

“…However, the safety of ANGPTL4 knockdown has been called into question due to severe lymphadenopathy observed in animals placed on high-fat diets (27,28). Intriguingly, humans with loss-of-function mutations in ANGPTL4 do not appear to be at an increased risk for lymphadenopathy (25,26). Therefore, additional research is needed to assess whether specifically blocking ANGPTL4 inhibition of LPL can be a viable treatment for hypertriglyceridemia.…”

“…Individuals with hypobetalipoproteinemia-2 appear to have few negative health effects and have motivated the development of novel antisense oligonucleotide therapeutics that silence ANGPTL3 expression (22,24). By comparison, inactivating mutations in ANGPTL4 result in a slightly different lipid profile with low levels of plasma triglycerides, high levels of HDL cholesterol, and no apparent effect on LDL cholesterol (19,25,26). Previous studies using either antibody to silence ANGPTL4 in monkeys or the genetic loss of ANGPTL4 in mice recapitulate low levels of plasma triglycerides seen in humans with loss-of-function ANGPTL4 mutations (25,27).…”

“…However, both ANGPTL4 knockdown monkeys and knockout mice inexplicably developed severe mesenteric lymphadenitis, or inflammation in the abdominal lymph nodes, when placed on a high-fat diet (25,27,28). Individuals with loss-of-function mutations in ANGPTL4 do not have increased rates of lymphadenopathy, and the animals do not develop this phenotype on standard chow or low-fat diets (25,26).…”

Future directions for high‐throughput splicing assays in precision medicine

“…Lastly, large data sets containing genetic variants for screening by MPRAs often lack corresponding phenotypic or other relevant MyCode participants are also consented for recontact for additional research which allows for additional clinical evaluation with more targeted phenotyping to supplement the rich data set that already exists in the EHR. DiscovEHR has already been proven to be a tremendous resource for genomic discovery (Abul-Husn et al, 2018; Gusarova et al, 2018;Verma et al, 2019).…”

RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

“…Similarly, we also chose some well-known IR-related genes from the sequencing analysis and detected their expression by qPCR. Pyruvate dehydrogenase kinase isoenzyme 4 (Pdk4) [35,36],and angiopoietin like 4 (Angptl4) [37], which were reported in promotion of IR, were observed up-regulated in the PA-treated C2C12 myotubes as shown in Supplementary Figure S2A,B. In contrary, protein kinase AMP activated gamma 3 (Prkag3) [38] and glucose transporter member 4 (Glut4) (also named Slc2a4) [39][40][41], whose deficiency were associated with IR, were observed with the decreased tendency in the PA-treated C2C12 myotubes as shown in Supplementary Figure S2C,D and Glut4 expression was down-regulated significantly.…”