Hepatokines, bile acids and ketone bodies are novel Hormones regulating energy homeostasis

Abstract

Current views show that an impaired balance partly explains the fat accumulation leading to obesity. Fetal malnutrition and early exposure to endocrine-disrupting compounds also contribute to obesity and impaired insulin secretion and/or sensitivity. The liver plays a major role in systemic glucose homeostasis through hepatokines secreted by hepatocytes. Hepatokines influence metabolism through autocrine, paracrine, and endocrine signaling and mediate the crosstalk between the liver, non-hepatic target tissues, and the brain. The liver also synthetizes bile acids (BAs) from cholesterol and secretes them into the bile. After food consumption, BAs mediate the digestion and absorption of fat-soluble vitamins and lipids in the duodenum. In recent studies, BAs act not simply as fat emulsifiers but represent endocrine molecules regulating key metabolic pathways. The liver is also the main site of the production of ketone bodies (KBs). In prolonged fasting, the brain utilizes KBs as an alternative to CHO. In the last few years, the ketogenic diet (KD) became a promising dietary intervention. Studies on subjects undergoing KD show that KBs are important mediators of inflammation and oxidative stress. The present review will focus on the role played by hepatokines, BAs, and KBs in obesity, and diabetes prevention and management and analyze the positive effects of BAs, KD, and hepatokine receptor analogs, which might justify their use as new therapeutic approaches for metabolic and aging-related diseases.

Keywords: GPBAR1; bile acids; fasting; hepatokines; ketogenic diet.

Figure 1

Interaction between hepatokines and BAs in nutrient and energy homeostasis. Legend for Figure 1 Overall events involved in the function of bile acids (BAs) acting as signaling molecules and receptor ligands of farnesoid X receptor (FXR) and the G protein–coupled receptor 1 (GPBAR–1). In the left box, the steps involved in BA biosynthesis, secretion, storage, intestinal flow, absorption, colonic biotransformation and fecal loss are listed, as part of the enterohepatic circulation of BAs. The location of FXR and GPBAR–1 (TGR5) are shown in the liver, intestine, and several other tissues with respect to the control of BAs on: 1. hepatic biosynthesis of primary BAs via the rate–limiting enzyme 7a–hydroxylase (CYP7A1) and CYP8B1 controlled negatively by the small heterodimer partner (SHP): cholic acid (CA) and chenodeoxycholic acid (CDCA), 2. intestinal release of FXR–mediated secretion of the fibroblast growth factor 19 (FGF19, known as FGF15 in mice), which circulates to the liver and reduces the expression of CYP7A1 to inhibit hepatic BA synthesis through FXR, 3. Intestinal GPBAR–1–mediated release of peptide YY (PYY), glucagon–like peptide 1 (GLP–1) and glucagon–like peptide 2(GLP–2). Recent studies show that Fetuin–B is playing additional roles through its interaction with Farnesoid X Receptor (FXR). In studies utilizing microarray technology Fetuin–B acts as a FXR agonist–regulated gene. Several metabolic functions (boxes on the right). Adapted from modified by Garruti et al. for Front Endocrinol.

Figure 2

Mechanism for physiological effects of hepatokines in target tissues. Legend for Figure 2 Some hepatokines signal the brain to modulate body weight homeostasis and food intake, while others act on adipose tissues and muscle to regulate lipid and glucose homeostasis. However, liver is also the main site of production of bile acids (BAs). In the figure we depicted the potential molecular mechanisms of crosstalk between nuclear receptors LXR and FXR–SHP–LRH–1 regulatory cascade in the liver and intestine. Bile acids are the natural ligands for FXR, which regulates transcription by binding as a heterodimer with RXRs. This step results in increased SHP expression. SHP in turn inhibits LRH–1, preventing the activation of target genes that participate in bile acid and fatty acid synthesis. In the absence of bile acids, LRH–1 acts together with LXR to stimulate bile acid synthesis. The important pathways in the intestine that contribute to modulation of bile acid synthesis are also depicted. There is a bile–acid–mediated activation of intestinal FXR and, as a result, the release of FGF15 in the small intestine. The secreted FGF15 by the intestine circulates to the liver, likely through the portal circulation or lymph flow and induces the activation of FGFR4 in the liver. The FGF15/FGFR4 pathway synergizes with SHP in vivo to repress CYP7A1 expression. Abbreviations: AMPK, adenosine monophosphate–activated protein kinase, ANGPTL6, angiopoietin–like 6,BAs: bile acids, FGF: fibroblast growth factor, FGFR4: FGF receptor 4, FGF21, fibroblast growth factor 21, FST, follistatin, FXR: farnesoid X receptor, GDF15, growth differentiation factor 15, IGF1, insulin–like growth factor 1, LCN13, lipocalin 13, LRH–1: liver receptor homologue–1, LXR: liver X receptor, RXR: retinoid X receptors, SHP: short heterodimer partner, SMOC1, SPARC–related modular calcium–binding protein–1, TSK, Tsukushi, UCP1, uncoupling protein 1 Adapted from Reference and modified by Garruti et al. for Front Endocrinol.