Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man

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• 作者：Adriaan  ; G. Holleboom¹ ;   ; ¹⁵ ; Helen Karlsson⁵ ;   ; ⁸ ;   ; ¹⁵ ; Ruei-Shiuan Lin⁶ ; Thomas  ; M. Beres⁶ ; Jeroen  ; A. Sierts² ; Daniel  ; S. Herman⁷ ; Erik  ; S.G. Stroes¹ ; Johannes  ; M. Aerts³ ; John  ; J.P. Kastelein¹ ; Mohammad  ; M. Motazacker² ; Geesje  ; M. Dallinga-Thie¹ ;   ; ² ; Johannes  ; H.M. Levels² ; Aeilko  ; H. Zwinderman⁴ ; Jonathan  ; G. Seidman⁷ ; Christine  ; E. Seidman⁷ ; Stefan Ljunggren⁸ ; Dirk  ; J. Lefeber⁹ ;   ; ¹⁰ ;   ; ¹¹ ; Eva Morava¹¹ ;   ; ¹² ; Ron  ; A. Wevers¹⁰ ;   ; ¹¹ ; Timothy  ; A. Fritz¹³ ; Lawrence  ; A. Tabak⁶ ; Mats Lindahl⁸ ; G.  ; Kees Hovingh¹ ;   ; ^{g.k.hovingh@amc.uva.nl} ; Jan  ; Albert Kuivenhoven² ;   ; ¹⁴ ;   ; ^{j.a.kuivenhoven@umcg.nl}
• 刊名：Cell Metabolism
• 出版年：2011
• 出版时间：7 December 2011
• 年：2011
• 卷：14
• 期：6
• 页码：811-818
• 全文大小：484 K

文摘

Summary

Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which?removes the sialic acids from its glycan chain?decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.