Key result
Nontruncating missense APOB mutations impaired hepatic secretion of apoB proteins and down-regulated lipogenesis genes, which may reduce fat accumulation in the FHBL liver.
Feedback inhibition of hepatic lipogenesis and post-ER degradation of misfolded apoB proteins help prevent fat accumulation in FHBL livers with APOB missense mutations.
Suggests mutation-specific hepatic protection in FHBL models; leaves open human translation and therapeutic targeting.
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.
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Zhong et al. (2009) studied Familial hypobetalipoproteinemia (FHBL). Nontruncating missense APOB mutations (A31P, G275S, L324M, G912D, and G945S) vs. Wild type APOB was evaluated on Impairment in secretion of mutant apoB proteins. Nontruncating missense APOB mutations impaired hepatic secretion of apoB proteins and down-regulated lipogenesis genes, which may reduce fat accumulation in the FHBL liver.
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