Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

被引：41

作者：

Aikio, Mari ^{[1
,2
]}

Elamaa, Harri ^{[1
,2
]}

Vicente, David ^{[1
,2
]}

Izzi, Valerio ^{[1
,2
]}

Kaur, Inderjeet ^{[1
,2
]}

Seppinen, Lotta ^{[1
,2
]}

Speedy, Helen E. ^{[3
,4
]}

Kaminska, Dorota ^{[5
]}

Kuusisto, Sanna ^{[2
,6
]}

Sormunen, Raija ^{[2
,7
]}

Heljasvaara, Ritva ^{[1
,2
]}

Jones, Emma L. ^{[3
,4
]}

Muilu, Mikko ^{[8
]}

Jauhiainen, Matti ^{[8
]}

Pihlajamaki, Jussi ^{[5
,9
]}

Savolainen, Markku J. ^{[2
,6
]}

Shoulders, Carol C. ^{[3
,4
]}

Pihlajaniemi, Taina ^{[1
,2
,6
]}

机构：

[1] Univ Oulu, Oulu Univ Hosp, Fac Biochem & Mol Med, Oulu Ctr Cell Matrix Res, FI-90014 Oulu, Finland

[2] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, FI-90014 Oulu, Finland

[3] Queen Mary Univ London, Ctr Endocrinol, William Harvey Res Inst, London EC1M 6BQ, England

[4] Barts & London Queen Marys Sch Med & Dent, London EC1M 6BQ, England

[5] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Dept Clin Nutr, FI-70211 Kuopio, Finland

[6] Univ Oulu, Clin Res Ctr, Inst Clin Med, FI-90014 Oulu, Finland

[7] Univ Oulu, Oulu Univ Hosp, Dept Pathol, FI-90014 Oulu, Finland

[8] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, FI-00290 Helsinki, Finland

[9] Kuopio Univ Hosp, Clin Nutr & Obes Ctr, Dept Med, FI-70211 Kuopio, Finland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 30期

基金：

英国医学研究理事会; 芬兰科学院;

关键词：

KNOBLOCH-SYNDROME; PPAR-GAMMA; ENDOGENOUS INHIBITOR; HEPATIC LIPASE; EXPRESSION; GENE; ADIPOGENESIS; BINDING; IDENTIFICATION; ANGIOGENESIS;

D O I：

10.1073/pnas.1405879111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had similar to 50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzled-like sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen alpha 1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

引用

页码：E3043 / E3052

页数：10

共 55 条

[41] IDENTIFICATION OF 3 N-TERMINAL ENDS OF TYPE-XVIII COLLAGEN CHAINS AND TISSUE-SPECIFIC DIFFERENCES IN THE EXPRESSION OF THE CORRESPONDING TRANSCRIPTS - THE LONGEST FORM CONTAINS A NOVEL MOTIF HOMOLOGOUS TO RAT AND DROSOPHILA FRIZZLED PROTEINS [J].