Farnesoid X receptor–induced lysine‐specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity

Abstract

Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. BA homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary bile acid receptor, farnesoid X receptor (FXR), and small heterodimer partner (SHP) that inhibits BA synthesis by recruiting repressive histone-modifying enzymes. Although histone modifiers have been shown to regulate BA-responsive genes, their in vivo functions remain unclear. Here we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated FXR, is recruited to BA synthetic genes, Cyp7a1 and Cyp8b1, and the BA uptake transporter gene, Ntcp, and removes a gene-activation mark, tri-methylated histone H3 lysine-4, leading to gene repression. LSD1 recruitment was dependent on SHP, and LSD1-mediated demethylation of H3K4-me3 was required for additional repressive histone modifications, H3K9/K14 deacetylation and H3K9 methylation. BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenoviral-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum AST/ALT levels, and hepatic inflammation. This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the FXR and SHP that reduces hepatic BA levels and protects the liver against BA toxicity.

A postprandial FGF 19‐ SHP ‐ LSD 1 regulatory axis mediates epigenetic repression of hepatic autophagy

“…The current study reveals multiple transcriptionally regulated pathways that are initiated after feeding by the bile acid nuclear receptor FXR and further demonstrate the link between bile acid signaling and the autophagic pathway. Upon food intake, bile acid‐activated FXR directly represses hepatic autophagy genes (Lee et al , ; Seok et al , ), but also induces the expression of SHP, LSD1 (Kim et al , ), and FGF15/19 (Inagaki et al , ). Thus, direct FXR repression of autophagy would be expected to precede that by FXR‐induced SHP, LSD1, and FGF15/19.…”

Bile acid hepatotoxicity: Epigenetics comes to the rescue

“…3 First, they discovered functional FXR binding motifs, inverted repeat element 1, in the intron regions of the Lsd1 gene. 2 They also found that pharmacological or physiological activation of FXR signaling induced expression of Lsd1 in mouse liver. Farnesoid X receptor-induced Lsd1 directly interacted with SHP and enhanced gene repression by SHP in reporter assays.…”

“…In the current issue of HEPATOLOGY, Kim et al add to the complexity of SHP-mediated transcriptional repression involved in fine-tuning of bile acid homeostasis by linking demethylation of a histone activation mark with FXR-dependent gene repression through the induction of SHP. 2 They showed convincingly that FXR induces, with the help of SHP, the expression and recruitment of the lysine-specific histone demethylase LSD1 to the CYP7a1 and CYP8b1 loci, leading to epigenetic repres-sion of bile synthesis. Lysine (K)-specific demethylase 1 (LSD1) is a histone demethylase that demethylates both lysine 4 (H3K4me) and lysine 9 (H3K9me) of histone H3 NH 2 -terminal tails, potentially acting as a coactivator or a corepressor, depending on the cellular context.…”

“…LSD1 and HDAC1 but that SHP is likely the dominant factor in LSD1 recruitment. 2 Why does the expression of Lsd1 involving modification of only a single histone lysine residue have such a profound effect on bile acid homeostasis? The answer is not entirely clear, but inferences may be drawn from the known critically important effects of the H3K4 site on transcription.…”

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

“…SHP does not have a DNA binding domain but acts as a corepressor for numerous transcriptional factors . SHP links elevated hepatic BA levels to epigenetic repression of genes involved in BA synthesis and reuptake, including cholesterol 7α hydroxylase ( Cyp7a1 ), sterol 12α hydroxylase ( Cyp8b1 ), and sodium/taurocholate cotransporting polypeptide ( Ntcp ), by recruiting repressive histone‐modifying proteins to these genes . The gene regulatory functions and protein stability of SHP are enhanced by a late fed‐state intestinal hormone, fibroblast growth factor‐19 (FGF19, mouse FGF15) .…”