Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Mutations in the receptor that clears circulating LDL-C result in a devastating condition known as familial hypercholesterolemia (FH), which is characterized by extremely high levels of LDL-C and markedly accelerated CVD mortality. Recently, the United States Food and Drug Administration approved a somewhat controversial new therapy called mipomersen for patients suffering from FH. Mipomersen is one of the first antisense oligonucleotide (ASO)–based therapies that specifically targets the knockdown of the major structural protein of LDL-C known as apolipoprotein B (apoB).
Given the central role that apoB plays in removing lipids such as cholesterol and triglycerides from the liver, many experts in the field warned that hepatic steatosis (i.e., fatty liver) would be an obvious potential side effect of this drug. However, both rodent and human studies have shown that mipomersen treatment paradoxically does not result in hepatic steatosis, though the mechanisms behind this have been elusive. Now, Conlon et al. provide evidence in mice that ASO-mediated knockdown of apoB stimulates a compensatory up-regulation of endoplasmic reticulum (ER)–associated autophagy, functionally channeling triglycerides towards lysosomal degradation.
To identify mechanisms by which mipomersen fails to induce hepatic steatosis, Conlon et al. treated mice with a mouse-targeted apoB ASO and carefully examined subcellular accumulation of lipids, as well as markers of autophagic flux in the liver. In early stages of apoB knockdown, there was an apparent activation of ER stress and accumulation of autophagosome-like structures. As treatment was prolonged, activation of ER-associated autophagy was coupled to increased lipolysis of triglycerides, which ultimately resulted in delivery of fatty acid substrate for mitochondrial oxidation.
This study provides insights into a compensatory pathway in the liver that senses abnormal accumulation of triglycerides in the ER to activate lysosomal triglyceride degradation. This important work reveals molecular mechanisms regulating hepatic triglyceride storage and secretion and provides a long-awaited explanation for why mipomersen does not promote hepatic steatosis.
D. M. Conlon et al., Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis. J. Clin. Invest. 10.1172/JCI86028 (2016). [Full Text]
- Copyright © 2016, American Association for the Advancement of Science