Wu_2026_Dis.Model.Mech__

Lipoprotein lipase (LPL) is the rate-limiting enzyme that hydrolyzes triglycerides within circulating lipoproteins. LPL dysfunction leads to familial LPL deficiency, which is characterized by chylomicronemia and high risk for acute pancreatitis. Although cell culture studies indicate that the protease furin inactivates LPL by cleavage, the physiological relevance of this process remains unclear. In this study, we investigated the impact of furin-mediated LPL cleavage in vivo using inducible knockout mouse models and gene therapy. After identifying the tissue-specific prevalence of LPL cleavage, we compared mice expressing a furin-resistant LPL mutant versus furin-sensitive LPL. Our results demonstrate that furin-resistant LPL lowers longitudinal plasma triglyceride levels without causing adverse effects such as hepatic steatosis. These findings highlight that engineered furin resistance is a viable strategy to enhance LPL's metabolic function.