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

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

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 9

ER autophagy–mediated FA oxidation prevents steatosis when apoB synthesis is inhibited but MTP is active.

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ER autophagy–mediated FA oxidation prevents steatosis when apoB synthesi...
(A) In control ASO–treated mice, MTP lipidates nascent apoB as it translocates across the ER. Further continuous lipidation or fusion with ER luminal droplets results in the formation of VLDL, which exits the ER on the way to secretion. Some newly synthesized lipids are transferred to cytosolic LDs in control ASO–treated mice. (B) In MTP ASO–treated mice, the transfer of lipid from the ER membrane into the lumen of the ER is prevented, apoB protein is cotranslationally degraded, VLDL assembly and secretion is blocked, and newly synthesized lipids can only be transferred into cytosolic LDs. (C) In apoB ASO–treated mice, lipid transferred by MTP into the lumen of the ER accumulates in the absence of apoB. This stimulates the formation of double-membrane autophagosomes that engulf lipid-filled regions of the ER. The autophagosomes fuse with lysosomes, where lipids, including TG, are hydrolyzed by acidic lipases. The FA generated by lipolysis become available for oxidation in mitochondria. PDI, protein disulfide isomerase; Lp, lipoprotein.