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Specific Collagen XVIII Isoforms Promote Adipose Tissue PNAS PLUS Accrual Via Mechanisms Determining Adipocyte Number and Affect Fat Deposition

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Specific Collagen XVIII Isoforms Promote Adipose Tissue PNAS PLUS Accrual Via Mechanisms Determining Adipocyte Number and Affect Fat Deposition Specific collagen XVIII isoforms promote adipose tissue PNAS PLUS accrual via mechanisms determining adipocyte number and affect fat deposition Mari Aikioa,b,1, Harri Elamaaa,b,1, David Vicentea,b, Valerio Izzia,b, Inderjeet Kaura,b, Lotta Seppinena,b, Helen E. Speedyc, Dorota Kaminskad, Sanna Kuusistob,e, Raija Sormunenb,f, Ritva Heljasvaaraa,b, Emma L. Jonesc, Mikko Muilug, Matti Jauhiaineng, Jussi Pihlajamäkid,h, Markku J. Savolainenb,e, Carol C. Shouldersc,2, and Taina Pihlajaniemia,b,2 aFaculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, bBiocenter Oulu, eDepartment of Internal Medicine, Clinical Research Center, Institute of Clinical Medicine, and fDepartment of Pathology, Oulu University Hospital, University of Oulu, FI-90014 Oulu, Finland; cCentre for Endocrinology, William Harvey Research Institute, Queen Mary University of London and Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; dDepartment of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland; gPublic Health Genomics Unit, National Institute for Health and Welfare, FI-00290 Helsinki, Finland; and hDepartment of Medicine, Clinical Nutrition and Obesity Center, Kuopio University Hospital, FI-70211 Kuopio, Finland Edited* by Darwin J. Prockop, Texas A&M Health Science Center, Temple, TX, and approved June 16, 2014 (received for review April 1, 2014) − − Collagen XVIII is an evolutionary conserved ubiquitously ex- Col18a1 / mice recapitulate the human eye disease of Knobloch pressed basement membrane proteoglycan produced in three syndrome, including delayed regression of the hyaloid vessels and isoforms via two promoters (P). Here, we assess the function of impaired angiogenesis of retinal vessels (8, 9). Moreover, on − − the N-terminal, domain of unknown function/frizzled-like sequen- a specific background, Col18a1 / mice have increased suscep- ces unique to medium/long collagen XVIII by creating P-specific tibility to hydrocephalus associated with broadening of the epi- null mice. P2-null mice, which only produce short collagen XVIII, thelial BM of the choroid plexuses (10). Curiously, these mice developed reduced bulk-adiposity, hepatic steatosis, and hypertri- also display postprandial hyperlipidemia (11) and, on an apo- P1 − − glyceridemia. These abnormalities did not develop in -null mice, lipoprotein E (ApoE) / background, develop severe athero- which produce medium/long collagen XVIII. White adipose tissue sclerosis because of increased plaque angiogenesis and CELL BIOLOGY samples from P2-null mice contain larger reserves of a cell popu- permeability of the vasculature to lipids (12). Thus, collagen lation enriched in early adipocyte progenitors; however, their XVIII is obligatory for controlling blood vessel formation in the embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipo- eye, and may also partake in BM or cell-signaling functions in cytes produced striking increases in P2 gene-products and dramatic extraocular tissues. falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferenti- An unresolved issue concerns the physiological roles of the ation of mature adipocytes produced reciprocal changes in P1 and three distinct N-terminal, noncollagenous (NC) domains of P2 transcript levels. P2-derived gene-products containing frizzled- collagen XVIII (13, 14). The “short form,” which is present in like sequences bound the potent adipogenic inhibitor, Wnt10b, in most vascular and epithelial BMs and around smooth and skel- vitro. Previously, we have shown that these same sequences bind etal muscle (15), derives from promoter (P) 1 transcripts and Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in lacks, through exon skipping, exon 3-encoded amino acid residues. visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes Significance to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, A previously unrecognized role is described for collagen XVIII— and interaction between hepatic apolipoprotein E and this proteo- a ubiquitous, structurally complex basement membrane pro- P2- glycan is lost in null mice. These results describe a previously teoglycan—in supporting preadipocyte differentiation and the unidentified extracellular matrix-directed mechanism contributing maintenance of this differentiated state, and hence the size and to the control of the multistep adipogenic program that determines lipid-clearing/storage functions of white adipose tissue depots. the number of precursors committing to adipocyte differentiation, Specific lack of medium and long isoforms of this nonfibrillar the maintenance of the differentiated state, and the physiological collagen in mice led to reduced adiposity, ectopic deposition of fat consequences of its impairment on ectopic fat deposition. in liver, and elevated very low-density lipoprotein-triglyceride levels. The finding of a previously unidentified extracellular ollagen XVIII, one of the multiplexin subfamily of nonfibrillar mechanism contributing to control of adipogenesis is expected to Ccollagens (1), is a component of basement membranes (BM) promote understanding of the molecular and functional bases of of both epithelial and endothelial cells. Collagen XVIII has human hyperlipidemic syndromes associated with fatty liver. attracted much interest on several accounts. It has the structural properties of both a collagen and a proteoglycan (2); it contains Author contributions: M.A., H.E., D.V., V.I., I.K., L.S., H.E.S., D.K., S.K., R.S., R.H., E.L.J., M.M., M.J., J.P., M.J.S., C.C.S., and T.P. designed research; M.A., H.E., D.V., V.I., I.K., L.S., the antiangiogenic molecule, endostatin (3), and its coding H.E.S., D.K., S.K., R.S., R.H., E.L.J., M.M., M.J., J.P., M.J.S., C.C.S., and T.P. performed re- gene, collagen α1 (XVIII) (COL18A1), is mutated in the rare, search; M.A., H.E., D.V., V.I., I.K., L.S., R.H., and T.P. contributed new reagents/analytic recessively inherited Knobloch syndrome (4). This condition is tools; M.A., H.E., D.V., V.I., I.K., L.S., H.E.S., D.K., S.K., R.S., R.H., E.L.J., M.M., M.J., J.P., M.J.S., C.C.S., and T.P. analyzed data; and M.A., H.E., D.V., V.I., H.E.S., D.K., S.K., R.S., R.H., E.L.J., characterized by high myopia and vitro-retinal degeneration, M.J., J.P., M.J.S., C.C.S., and T.P. wrote the paper. and occasionally by occipital encephalocele (5, 6). Epilepsy, The authors declare no conflict of interest. renal anomalies, lung hypoplasia, and acute lymphoblastic *This Direct Submission article had a prearranged editor. leukemia also figure in isolated cases (5, 7) but it remains to be 1M.A. and H.E. contributed equally to this work. established which, if any, of these diverse features result from 2To whom correspondence may be addressed. Email: [email protected] or disturbances of collagen XVIII-mediated BM functions, the [email protected]. antiangiogenic actions of endostatin, or hitherto unsuspected This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. biological activities of this proteoglycan. 1073/pnas.1405879111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1405879111 PNAS Early Edition | 1of10 Downloaded by guest on September 27, 2021 In contrast, the medium and long variants, abundant in liver Results sinusoids (15), are generated from a downstream promoter (P2) Ablating Medium/Long Collagen XVIII Modulates Adiposity and Liver and alternative splicing of exon 3 (16). Medium and long collagen Weights. Fig. 1A provides a schematic of the collagen XVIII XVIII possess an N-terminal domain of unknown function isoforms encoded by P1- and P2-derived Col18a1 transcripts − − (DUF), whereas the “long” isoform alone has a domain-sharing (Fig. 1B). To complement studies on Col18a1 / mice we produced structural identity with the extracellular domain of frizzled (Fz) mice expressing only P1 or P2 transcripts, as depicted in Fig. S1. P1/P1 receptors (17). P2-derived gene-products also undergo proteolytic Specific inactivation of exon 1 (P1-null, Col18a1 ) and deletion P2/P2 processing, thereby producing Fz-cysteine rich sequences that of exon 3 (P2-null, Col18a1 ) were confirmed by Southern blot bind Wnt3a in vitro and inhibits Wnt/B-catenin-signaling and and PCR analysis (Fig. S1) plus real-time quantitative-PCR (RT- downstream gene expression (18). qPCR) of liver, epididymal (e)WAT, and kidney RNA (Fig. S2). In this study, we have further investigated the consequences of Neither P-null mouse models displayed compensatory rises in Col18a1 RNA from the nontargeted promoter (Fig. S2). complete lack of collagen XVIII and examined the individual −/− roles of P1- and P2-derived gene-products. Mice lacking P2- Col18a1 mice transcribed varying amounts of RNA from derived DUF/Fz sequences exhibit reduced adiposity, manifesting both promoters (Fig. S2), potentially because of placing the inactivating cassette into a 3′ Col18a1 exon (8). as a reduction in the number of precursor cells that attain To further validate the quality of the newly created Col18a1 a mature fat-cell phenotype, increased deposition of fat in liver, mouse lines, we immunofluorescently stained the kidney, an and elevated very low-density lipoprotein (VLDL)-triglyceride organ that expresses all
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