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Nonsynonymous Mutations within APOB in Human Familial Hypobetalipoproteinemia: EVIDENCE FOR FEEDBACK INHIBITION OF LIPOGENESIS AND POSTENDOPLASMIC RETICULUM DEGRADATION OF APOLIPOPROTEIN B

Zhong, Shumei ; Magnolo, Antonia Lucia ; Sundaram, Meenakshi ; Zhou, Hu ; Yao, Erik F ; Di Leo, Enza ; Loria, Paola ; Wang, Shuai ; Bamji-Mirza, Michelle ; Wang, Lisheng ; McKnight, C. Jamie ; Figeys, Daniel ; Wang, Yuwei ; Tarugi, Patrizia ; Yao, Zemin

The Journal of biological chemistry, 2010-02, Vol.285 (9), p.6453-6464 [Periódico revisado por pares]

United States: American Society for Biochemistry and Molecular Biology

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Título:
Nonsynonymous Mutations within APOB in Human Familial Hypobetalipoproteinemia: EVIDENCE FOR FEEDBACK INHIBITION OF LIPOGENESIS AND POSTENDOPLASMIC RETICULUM DEGRADATION OF APOLIPOPROTEIN B
Autor: Zhong, Shumei ; Magnolo, Antonia Lucia ; Sundaram, Meenakshi ; Zhou, Hu ; Yao, Erik F ; Di Leo, Enza ; Loria, Paola ; Wang, Shuai ; Bamji-Mirza, Michelle ; Wang, Lisheng ; McKnight, C. Jamie ; Figeys, Daniel ; Wang, Yuwei ; Tarugi, Patrizia ; Yao, Zemin
Assuntos: Apolipoproteins B - genetics ; Apolipoproteins B - metabolism ; Autophagy ; Down-Regulation ; Endoplasmic Reticulum ; Feedback, Physiological ; Golgi Apparatus ; Heterozygote ; Humans ; Hypobetalipoproteinemia, Familial, Apolipoprotein B - genetics ; Hypobetalipoproteinemia, Familial, Apolipoprotein B - metabolism ; Italy ; Lipogenesis - genetics ; Liver - metabolism ; Molecular Bases of Disease ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; Mutation, Missense ; Protein Folding
É parte de: The Journal of biological chemistry, 2010-02, Vol.285 (9), p.6453-6464
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Canadian Research Chair of Proteomics and Systems Biology.
Recipient of a New Investigator award from CIHR.
Descrição: Five nontruncating missense APOB mutations, namely A31P, G275S, L324M, G912D, and G945S, were identified in heterozygous carriers of familial hypobetalipoproteinemia (FHBL) in the Italian population. To test that the FHBL phenotype was a result of impaired hepatic secretion of mutant apoB proteins, we performed transfection studies using McA-RH7777 cells stably expressing wild type or mutant forms of human apolipoprotein B-48 (apoB-48). All mutant proteins displayed varied impairment in secretion, with G912D the least affected and A31P barely secreted. Although some A31P was degraded by proteasomes, a significant proportion of it (although inappropriately glycosylated) escaped endoplasmic reticulum (ER) quality control and presented in the Golgi compartment. Degradation of the post-ER A31P was achieved by autophagy. Expression of A31P also decreased secretion of endogenous apoB and triglycerides, yet the impaired lipoprotein secretion did not lead to lipid accumulation in the cells or ER stress. Rather, expression of genes involved in lipogenesis was down-regulated, including liver X receptor α, sterol regulator element-binding protein 1c, fatty acid synthase, acetyl-CoA carboxylase 1, stearoyl-CoA desaturase 1, and lipin-1. These results suggest that feedback inhibition of hepatic lipogenesis in conjunction with post-ER degradation of misfolded apoB proteins can contribute to reduce fat accumulation in the FHBL liver.
Editor: United States: American Society for Biochemistry and Molecular Biology
Idioma: Inglês

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Nonsynonymous Mutations within APOB in Human Familial Hypobetalipoproteinemia: EVIDENCE FOR FEEDBACK INHIBITION OF LIPOGENESIS AND POSTENDOPLASMIC RETICULUM DEGRADATION OF APOLIPOPROTEIN B

Zhong, Shumei ; Magnolo, Antonia Lucia ; Sundaram, Meenakshi ; Zhou, Hu ; Yao, Erik F ; Di Leo, Enza ; Loria, Paola ; Wang, Shuai ; Bamji-Mirza, Michelle ; Wang, Lisheng ; McKnight, C. Jamie ; Figeys, Daniel ; Wang, Yuwei ; Tarugi, Patrizia ; Yao, Zemin

United States: American Society for Biochemistry and Molecular Biology

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