SUMMARY The lipolytic processing of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) is the central event in plasma lipid metabolism, providing lipids for storage in adipose tissue and fuel for vital organs such as the heart. LPL is synthesized and secreted by myocytes and adipocytes but then finds its way into the lumen of capillaries, where it hydrolyzes lipoprotein triglycerides. The mechanism by which LPL reaches the lumen of capillaries represents one of the most persistent mysteries of plasma lipid metabolism. Here, we show that GPIHBP1 is responsible for the transport of LPL into capillaries. In Gpihbp1-deficient mice, LPL is mislocalized to the interstitial spaces surrounding myocytes and adipocytes. Also, we show that GPIHBP1 is located at the basolateral surface of capillary endothelial cells and actively transports LPL across endothelial cells. Our experiments define the function of GPIHBP1 in triglyceride metabolism and provide a mechanism for the transport of LPL into capillaries.
Lamin B1 is essential for neuronal migration and progenitor proliferation during the development of the cerebral cortex. The observation of distinct phenotypes of Lmnb1- and Lmnb2-knockout mice and the differences in the nuclear morphology of cortical neurons in vivo suggest that lamin B1 and lamin B2 play distinct functions in the developing brain.
Nuclear lamins are components of the nuclear lamina, a structural scaffolding for the cell nucleus. Defects in lamins A and C cause an array of human diseases, including muscular dystrophy, lipodystrophy, and progeria, but no diseases have been linked to the loss of lamins B1 or B2. To explore the functional relevance of lamin B2, we generated lamin B2-deficient mice and found that they have severe brain abnormalities resembling lissencephaly, with abnormal layering of neurons in the cerebral cortex and cerebellum. This neuronal layering abnormality is due to defective neuronal migration, a process that is dependent on the organized movement of the nucleus within the cell. These studies establish an essential function for lamin B2 in neuronal migration and brain development.brain | lissencephaly | neuronal migration | nuclear envelope | nuclear lamina T he nuclear lamina is an intermediate filament meshwork lying beneath the inner nuclear membrane that provides a structural scaffolding for the nucleus (1). The lamina is also important for other processes, including gene transcription, chromatin organization, nuclear pore distribution, nuclear envelope assembly, and tethering of the nucleus to the cytoskeleton (1, 2). The main components of the nuclear lamina are nuclear lamins, a class of intermediate filament proteins that is generally divided into two groups, A-type (lamins A and C) and B-type (lamins B1 and B2) (3, 4). Lamins A and C are produced from LMNA by alternative splicing, whereas lamins B1 and B2 are encoded by distinct genes, LMNB1 and LMNB2, respectively. Lamins B1 and B2 are expressed in all cells and throughout development, whereas lamins A and C are expressed in differentiated cells, beginning at midgestation (3).Interest in the nuclear lamins has intensified with the discovery that over a dozen human diseases, including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria, are caused by mutations in LMNA (5-7). To date, more than 340 missense, nonsense, frameshift, and splicing mutations have been identified (5). In contrast, no human diseases have been linked to these types of mutations in LMNB1 and LMNB2, and, so far, the only clear-cut association between B-type lamins and disease has been the finding of LMNB1 gene duplications in autosomal-dominant leukodystrophy (8).The paucity of "lamin B diseases" is probably not due to complete redundancy of lamins B1 and B2, as Lmnb1-deficient mice are small during embryonic development and die soon after birth with defects in lungs and bones (9). Also, Lmnb1-deficient fibroblasts display misshapen cell nuclei, aneuploidy, and early senescence (9). To further examine the functional importance of the B-type lamins, we generated Lmnb2-deficient mice.
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