Integrative analysis reveals multiple modes of LXR transcriptional regulation in liver

Abstract

The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRβ from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.

The LXRB-SREBP1 network regulates lipogenic homeostasis by controlling the synthesis of polyunsaturated fatty acids in goat mammary epithelial cells

“…8 B). This idea agrees with the observation in mouse liver that the binding of LXRs to hepatic genes has broad effects on the transcriptional landscape beyond its canonical function as an activator of lipid metabolism genes [ 20 ].…”

“…For instance, in mouse [ 12 ] and goats [ 14 ], ELOVL6 is suggested to be a target of SREBP1 because its promoter contains SREBP1 response element (SRE). Besides SREBP1, at least in non-ruminants, the transcription factor liver X receptor (LXR) is also involved in lipogenesis in an SREBP-dependent and -independent manner [ 20 ]. Upon activation by oxysterols or synthetic agonists in humans and rodents, LXR binds to LXR response elements (LXRE) in the promoters of target genes as a heterodimeric complex with retinoid X receptor, leading to transcription of lipogenic enzymes [ 21 ].…”

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

“…Studies have shown that when mice are fed a high-cholesterol diet, the deficiency of LXR leads to pathological accumulation of cholesterol in the liver. When mice are fed a normal chow diet, the loss of liver LXR mainly leads to metabolic disorder of fatty acids and phospholipids (Bideyan et al, 2022). LXR are involved in reduction of intestinal cholesterol absorption and increase of intestinal excretion via down-regulating Niemann-Pick C1-like 1 and elevating ABCG5/8 (Muscoli et al, 2022).…”

Regulation of Chromatin Accessibility by the Farnesoid X Receptor Is Essential for Circadian and Bile Acid Homeostasis In Vivo

“…For example, we did not observe a complete gain or loss of chromatin accessibility with FXR deletion at any of the differentially accessible regions. However, the changes in chromatin accessibility observed with FXR deletion were more pronounced relative to a loss of other nuclear receptors in the liver, such as LXR [ 36 ]. For instance, upon FXR deletion the vast majority (>95%) of statistically significant differentially accessible regions correspond to chromatin that is closing relative to the same regions in control hepatocytes.…”