Nonsynonymous mutations within APOB in human familial hypobetalipoproteinemia: evidence for feedback inhibition of lipogenesis and postendoplasmic reticulum degradation of apolipoprotein B.
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.
Zhong
Shumei
S
Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Magnolo
Antonia Lucia
AL
Sundaram
Meenakshi
M
Zhou
Hu
H
Yao
Erik F
EF
Di Leo
Enza
E
Loria
Paola
P
Wang
Shuai
S
Bamji-Mirza
Michelle
M
Wang
Lisheng
L
McKnight
C Jamie
CJ
Figeys
Daniel
D
Wang
Yuwei
Y
Tarugi
Patrizia
P
Yao
Zemin
Z
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
D001055:Apolipoproteins B; D050505:Mutant Proteins