Angiopoietin-like 4 promotes intracellular degradation of lipoprotein lipase in adipocytes

LPL hydrolyzes triglycerides in triglyceride-rich
lipoproteins along the capillaries of heart, skeletal muscle,
and adipose tissue. The activity of LPL is repressed by angiopoietin-
like 4 (ANGPTL4) but the underlying mechanisms
have not been fully elucidated. Our objective was to
study the cellular location and mechanism for LPL inhibition
by ANGPTL4. We performed studies in transfected
cells, ex vivo studies, and in vivo studies with Angptl4/
mice. Cotransfection of CHO pgsA-745 cells with ANGPTL4
and LPL reduced intracellular LPL protein levels, suggesting
that ANGPTL4 promotes LPL degradation. This conclusion
was supported by studies of primary adipocytes and
adipose tissue explants from wild-type and Angptl4/ mice.
Absence of ANGPTL4 resulted in accumulation of the mature-
glycosylated form of LPL and increased secretion of
LPL. Blocking endoplasmic reticulum (ER)-Golgi transport
abolished differences in LPL abundance between wild-type
and Angptl4/ adipocytes, suggesting that ANGPTL4 acts
upon LPL after LPL processing in the ER. Finally, physiological
changes in adipose tissue ANGPTL4 expression during
fasting and cold resulted in inverse changes in the amount of
mature-glycosylated LPL in wild-type mice, but not Angptl4/
mice. We conclude that ANGPTL4 promotes loss of intracellular
LPL by stimulating LPL degradation after LPL processing
in the ER