Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists

Publication date: Available online 6 December 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of LipidsAuthor(s): Yan Liu, Lahoucine Izem, Richard E. MortonAbstractApolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPARα nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and 4 potential PPARα binding sites clustered between nucleotides −2007 and −1961. ChIP analysis confirmed agonist-dependent binding of LXRα, PPARα, and RXRα to this hormone response element complex (HREc). A luciferase reporter containing the 2 kb 5′ APOF sequence was negatively regulated by LXR and PPARα ligands as seen in cells. This regulation was maintained in constructs lacking the ~1700 nucleotides between the HREc and the APOF proximal promoter. Mutations of the HREc that disrupted LXRα and PPARα binding led to the loss of reporter construct inhibition by agonists of these nuclear receptors. siRNA knockdown studies showed that APOF gene regulation by LXRα or PPARα agonists did not require an interaction between these two nuclear receptors. Thus, APOF is subject to negative...
Source: Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids - Category: Lipidology Source Type: research