Lnc-HC and ApoA1-AS
Other lncRNAs that have been associated to the regulation of cholesterol metabolism include Lnc-HC and ApoAl-AS (Halley et al. 2014; Lan et al. 2016). Lnc-HC is highly expressed in the liver and interacts with hnRNPA2B1 forming a RNA- protein complex, which can then bind to the target mRNAs, Cyp7a1 and Abcal (Lan et al. 2016). Inhibition of Lnc-HC increased Cyp7a1 and Abcal expression in hepatocytes, thus promoting cholesterol catabolism. Lnc-HC is conserved in humans and rodents and appears to be highly expressed in the liver and fat (Lan et al. 2016). These observations suggest that Lnc-HC might play a role in regulating lipid metabolism. However, additional studies in vivo are needed to define the role of Lnc-HC in regulating hepatic lipid homeostasis and lipoprotein metabolism. Another interesting finding is the identification of an antisense LncRNA (ApoAl-AS) encoded in the apolipoprotein gene cluster that contains four different transcripts including ApoAl, ApoA4, ApoA5, and ApoC3. ApoAl-AS controls the expression of the apoli- poprotein gene cluster epigenetically by recruiting histone-modifying enzymes (Halley et al. 2014). Targeting ApoAl-AS using ASOs increases ApoA1 expression in both monkey and human cells and enhances hepatic RNA and protein expression in African green monkeys. While these results are of interest, it is still not known whether the increase in circulating ApoA1 influences plasma lipid levels and/or lipoprotein metabolism.
Liver-specific triglyceride regulator (LncLSTR) was identified using an unbiased screen aimed to determine lncRNAs highly expressed in the liver (Li et al. 2015). Of note, specific inhibition of LncLSTR leads to a marked reduction in circulating TAG. Mechanistically, LncLSTR depletion increases apoC2 levels, an activator of the lipoprotein lipase (LPL), thus enhancing VLDL and chylomicron catabolism, leading to an increase in plasma TAG clearance (Li et al. 2015). Hepatic LncLSTR expression is regulated by FXR and forms a complex with TDP-43, thus regulating Cyp8b1 expression, a critical enzyme involved in bile acid synthesis.