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Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis
Donna M. Conlon, … , Jing Liu, Henry N. Ginsberg
Donna M. Conlon, … , Jing Liu, Henry N. Ginsberg
Published September 6, 2016
Citation Information: J Clin Invest. 2016;126(10):3852-3867. https://doi.org/10.1172/JCI86028.
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Research Article Metabolism Article has an altmetric score of 7

Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis

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Abstract

Inhibition of VLDL secretion reduces plasma levels of atherogenic apolipoprotein B (apoB) lipoproteins but can also cause hepatic steatosis. Approaches targeting apoB synthesis, which lies upstream of VLDL secretion, have potential to effectively reduce dyslipidemia but can also lead to hepatic accumulation of unsecreted triglycerides (TG). Here, we found that treating mice with apoB antisense oligonucleotides (ASOs) for 6 weeks decreased VLDL secretion and plasma cholesterol without causing steatosis. The absence of steatosis was linked to an increase in ER stress in the first 3 weeks of ASO treatment, followed by development of ER autophagy at the end of 6 weeks of treatment. The latter resulted in increased fatty acid (FA) oxidation that was inhibited by both chloroquine and 3-methyl adenine, consistent with trafficking of ER TG through the autophagic pathway before oxidation. These findings support the concept that inhibition of apoB synthesis traps lipids that have been transferred to the ER by microsomal TG transfer protein (MTP), inducing ER stress. ER stress then triggers ER autophagy and subsequent lysosomal lipolysis of TG, followed by mitochondrial oxidation of released FA, leading to prevention of steatosis. The identification of this pathway indicates that inhibition of VLDL secretion remains a viable target for therapies aiming to reduce circulating levels of atherogenic apoB lipoproteins.

Authors

Donna M. Conlon, Tiffany Thomas, Tatyana Fedotova, Antonio Hernandez-Ono, Gilbert Di Paolo, Robin B. Chan, Kelly Ruggles, Sarah Gibeley, Jing Liu, Henry N. Ginsberg

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Figure 8

ATG7 ASO inhibits autophagy in apoB ASO–treated mice but has no effect on either TG secretion or liver TG, despite an increase in liver weight.

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ATG7 ASO inhibits autophagy in apoB ASO–treated mice but has no effect o...
Increased ER stress and apoptosis were also evident. Apobec-1–KO mice were treated with apoB ASO for 6 weeks, and either control or ATG7 ASO was added for the final 3 weeks. (A) Liver homogenate was run on an SDS-PAGE and immunoblotted for ATG7, LC3, p62, and actin. N = 5–6 livers per group. (B) Triton WR1339 was injected i.v., blood samples were obtained every 30 minutes over the next 120 minutes, and plasma TG levels were measured. N = 2–3 mice per group. (C) Livers were weighed at the time of euthanization. N = 5–6 livers per group. *P < 0.05, by Student’s t test, for apoB plus ATG7 ASO versus apoB ASO control. (D) Liver lipids were extracted, and TG was measured enzymatically. N = 5–6 livers per group. (E) Primary hepatocytes were labeled with 14C OA for 2 hours, and then unlabeled chase media were added and collected every 4 hours over a 16-hour period. N = 6 wells from 2 mice per group. *P < 0.05, by Student’s t test, for apoB plus ATG7 ASO versus apoB ASO control. (F) The total amount of 14C OA oxidized over the 16-hour time points was summed for each group of mice. N = 6 wells from 2 mice per group. (G) Liver homogenate was run on a 10% SDS-PAGE and immunoblotted for the ER stress markers GRP78, p-eIF2α, and actin. N = 5–6 livers per group. (H) Liver homogenates were run on 8% or 12% SDS-PAGE and immunoblotted for various markers of apoptosis, either total or cleaved. N = 5–6 livers per group. All values represent the mean ± SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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