title: Nonsynonymous mutations within APOB in human familial hypobetalipoproteinemia: evidence for feedback inhibition of lipogenesis and postendoplasmic reticulum degradation of apolipoprotein B.
abstract: 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 alpha, 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.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhong
authors.forename: Antonia Lucia
authors.initials: AL
authors.lastname: Magnolo
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sundaram
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.forename: Erik F
authors.initials: EF
authors.lastname: Yao
authors.forename: Enza
authors.initials: E
authors.lastname: Di Leo
authors.forename: Paola
authors.initials: P
authors.lastname: Loria
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Michelle
authors.initials: M
authors.lastname: Bamji-Mirza
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.forename: C Jamie
authors.initials: CJ
authors.lastname: McKnight
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy; D015536:Down-Regulation; D004721:Endoplasmic Reticulum; D025461:Feedback, Physiological; D006056:Golgi Apparatus; D006579:Heterozygote; D006801:Humans; D052476:Hypobetalipoproteinemia, Familial, Apolipoprotein B / Q000235:genetics / Q000378:metabolism*; D007558:Italy; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D020125:Mutation, Missense; D017510:Protein Folding
chemical_list: D001055:Apolipoproteins B; D050505:Mutant Proteins