Abstract
Hypertriglyceridemia is a risk factor for the development of hypertension and diabetes. Plasma triglycerides (TGs) are hydrolyzed by lipoprotein lipase (LPL) to release free fatty acids for uptake into tissues. A circulating inhibitor of LPL is angiopoietin-like 4 (A4). A4 is expressed in liver and adipose and is present in circulation. In both humans and mice, A4 deficiency reduces plasma TGs. We previously reported that A4 deficient mice clear more TGs from plasma to adipose tissue. However, it is not clear if this effect is mediated by circulating ANGPTL4 or from local, adipose-derived A4. In this study we sought to characterize the effects of adipose- or liver-specific deletion of A4 on lipid homeostasis. Liver-specific or adipose-specific A4 knockout mice (A4-LivKO/AdipoKO) were generated by crossing A4 floxed mice (A4-fl/fl) with albumin-cre mice or adiponectin-cre mice, respectively. At 8 weeks of age, mice were randomized to either a normal chow diet (NCD) or a high fat diet (60% fat/kCal) for 12 weeks. TG levels (mg/dL) were significantly decreased in A4-AdipoKO mice at baseline (90±4) vs. A4-fl/fl (132±5). No differences were seen in A4-LivKO vs. A4-fl/fl mice (132±3 vs 130±4). After 12 weeks on diets, the A4-AdipoKO mice on NCD (92±6) and HFD (73±6) maintained lower plasma TG levels than A4-fl/fl mice (145±12) on NCD. No differences were seen in TG levels between A4-LivKO mice on HFD or NCD compared to A4-fl/fl mice. TG uptake was increased into adipose tissue of HFD fed A4-AdipoKO [(%-injected dose/mg tissue) (epididymal (eWAT) 0.82± 0.2 and brown adipose tissue (BAT) 1.74± 0.6)] compared to floxed controls on HFD (eWAT 0.44± 0.3 and BAT 0.93± 0.9). Liver-specific loss of ANGPTL4 had no differences in TG uptake from floxed controls on HFD. Overall, we anticipate that identifying tissue-specific contributions will be valuable in informing therapeutic approaches for treating hypertriglyceridemia.
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