Mice born with combined lipase deficiency (cld/cld) develop extreme hypertriglyceridemia and die within 3 days. They have very low levels (less than 5% normal) of lipoprotein lipase and hepatic lipase activities, their tissues are virtually devoid of fat, and 95% are tailless. Studies in vivo showed that brown adipose and other tissues of cld/cld mice synthesize normal sized lipoprotein lipase protein, but the enzyme is inactive and not transferred to capillaries, the normal site of action of this enzyme. The deficiency is caused by a recessive mutation (cld) in the T/t complex of chromosome 17. Cells cultured from brown adipose tissue of I-d old cld/cld and unaffected mice readily differentiated into brown adipocytes. Unaffected adipocytes contained and released lipoprotein lipase activity to the medium, whereas cld/cld adipocytes contained very little lipase activity and released none to the medium. cld/cld adipocytes contained 2 x normal amounts of lipoprotein lipase protein but, unlike unaffected cell, they released none to the medium. These findings demonstrate that (cld/cld brown adipocytes synthesize an inactive nonsecretable form of lipoprotein lipase. Liprotein lipase we found by immunocytochemistry in both endoplasmic reticulum and Golgi of unaffected brown adipocytes, whereas it was found only in endoplasmic reticulum of cld/cld adipocytes. Since lipoprotein lipase synthesized by cld/cld tissues is normal sized, these findings suggest that lipoprotein lipase synthesized in cld/cld adipocytes is glycosylated in endoplasmic reticulum, receiving a high-mannose type oligosaccharide. However, the lipase is not transported to the Golgi apparatus where normally the oligosaccharide component would be modified and the enzyme would become active and could be secreted by the cells.
