All-trans retinoic acid regulates hepatic bile acid homeostasis

Abstract

Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

“…Most actions of atRA are mediated via interactions with retinoic acid receptors (RARs) (Wolf, 2010;Yu et al, 2012), but atRA also activates the peroxisome proliferator-activated receptor (PPAR)-b/d (Shaw et al, 2003;Berry and Noy, 2007;Wolf, 2010). In addition, atRA induces the expression of the transcriptional repressor small heterodimer partner in the liver, resulting in broad effects on gene transcription, especially of genes responsible for bile acid metabolism and transport (Koh et al, 2014;Mamoon et al, 2014;Yang et al, 2014). The activation of multiple pathways by atRA likely leads to diverse effects on liver physiology, including altered lipid homeostasis.…”

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

“…FXR is involved in bile acid synthesis, and interestingly, bile acids and retinoic acid play similar roles in the regulation of insulin sensitivity and lipid homoeostasis . The induction of CYP4F by FXR activation could be attributable to two possible mechanisms: (1) Aside from the retinoid X receptor (RXR), retinoic acid, which activates FXR‐mediated pathways, can also induce the downstream metabolism of 1‐deoxysphingolipids . Furthermore, all‐trans retinoic acids have been shown to induce CYP4F expression in hepatocytes .…”

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

“…Mediated through RA receptors, such as retinoic acid receptors and RXRs, RA also regulates differentiation, metabolism, and development based on genome‐wide binding and gene expression profiling data (45, 67). In addition, RA has a profound effect on regulating genes involved in BA homeostasis (21). In WD‐fed mice, reduced RA signaling was accompanied by dysregulated BA synthesis.…”