Metabolic regulation of APOBEC-1 Complementation Factor Trafficking in Mouse Models of Obesity and its Positive Correlation with the Expression of ApoB Protein in Hepatocytes

Chad A. Galloway (1) , John Ashton (2) , Janet D. Sparks (3) , Robert A. Mooney (3) , Harold C. Smith (1, 3)

1 Department of Biochemistry and Biophysics
2 Department of Genetics
3 Department of Pathology and Laboratory Medicine

APOBEC-1 Complementation Factor (ACF) is an RNA-binding protein that interacts with mRNA to support RNA editing. ACF traffics between the cytoplasm and nucleus. It is retained in the nucleus in response to elevated serum insulin levels where it supports enhanced mRNA editing. In this report we tested whether ACF may have the ability to regulate nuclear export of mRNA to the sites of translation in the cytoplasm. Using mouse models of obesity-induced, insulin resistance and primary hepatocyte cultures we demonstrated that both nuclear retention of ACF and mRNA editing were reduced in the livers of hyperinsulinemic obese mice relative to lean controls. Coincident with an increase in the recovery of ACF in the cytoplasm was an increase in the proportion of total cellular mRNA recovered in cytoplasmic extracts. Cytoplasmic ACF from both lean controls and obese mouse livers was enriched in endosomal fractions associated with mRNA translation and ApoB lipoprotein assembly. Inhibition of ACF export to the cytoplasm resulted in nuclear retention of mRNA and reduced both intracellular and secreted ApoB protein in primary hepatocytes. The importance of ACF for modulating ApoB was supported by the finding that RNAi knockdown of ACF reduced ApoB secretion. An additional discovery from this study was the finding that leptin is a suppressor ACF expression. Dyslipidemia is a common pathology associated with insulin resistance that is in part due to the loss of insulin controlled secretion of lipid in ApoB-containing very low density lipoproteins. The data from animal models suggested that loss of insulin regulated ACF trafficking and leptin regulated ACF expression may make an early contribution to the overall pathology associated with very low-density lipoprotein secretion from the liver in obese individuals.

Mots clés: ACF; ApoB; APOBEC-1; ARE; BW; CNS; ELAV; ER; GFP; HDM; Il-6; LDLR; LDM; NLS; NMD; PKC; PP1; PPAR; RIA; RNAi; RRM; STAT; TNFα; VLDL; diabetes; insulin-resistance; APOBEC-1 Complementation Factor; apolipoprotein B; mRNA; Editing

Chad A. Galloway, John Ashton, Janet D. Sparks, Robert A. Mooney, Harold C. Smith. Metabolic regulation of APOBEC-1 Complementation Factor Trafficking in Mouse Models of Obesity and its Positive Correlation with the Expression of ApoB Protein in Hepatocytes. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, 1802 (11), pp.976. ⟨10.1016/j.bbadis.2010.06.003⟩. ⟨hal-00623310⟩