1931-P: New Insights Into Lipoprotein Lipase Maturation in the ER

Lipoprotein lipase (LPL) is a key enzyme responsible for the hydrolysis of triglycerides packed in lipoproteins, and defects in this process have been linked to the development of obesity-associated pathological conditions such as hyperlipidemia, atherosclerosis and stroke. However, our understanding of early events leading the maturation of nascent LPL protein remains limited. Here, we report a previously unappreciated crosstalk between ER-associated degradation (ERAD) and autophagy in controlling LPL maturation in the ER. Sel1L, an essential cofactor involved in ERAD, is required for the export of active LPL from the ER and prevents the formation of high molecular weight LPL aggregates. In the absence of Sel1L, autophagy is activated in adipocytes to limit the size of LPL aggregates in the ER. Deletion of autophagy in Sel1L-deficient adipocytes leads to the formation of large LPL foci in the ER. Thus, we conclude that Sel1L-Hrd1 ERAD and autophagy, most likely in the form of ER-phagy, synergistically control the biogenesis and aggregation of nascent LPL proteins. Ongoing studies aim to decipher how ERAD controls the activation of ER-phagy and how ER-phagy recognizes and degrades LPL aggregates. Disclosure S. Wu: None. M. Torres: None. L. Qi: None.