/pdf/the-lipophilic-bullet-hits-the-targets-medicinal-chemistry-5f1wikoz3q.pdf

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA1c. This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.

Beyond intestinal soap—bile acids in metabolic control

FXR signaling in the enterohepatic system.

Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) and the fasting transcriptional activator cAMP response element-binding protein (CREB) coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB-CRTC2 complex. This study identifies the new FXR-CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.

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Transcriptional regulation of autophagy by an FXR–CREB axis

https://www.medigraphic.com/pdfs/hepato/ah-2017/ahs171b.pdf

Bile Acid Physiology.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.25609

Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice

Small heterodimer partner (SHP) plays important roles in diverse biological processes by directly interacting with transcription factors and inhibiting their activities. SHP has been designated an orphan nuclear receptor, but whether its activity can be modulated by ligands has been a long-standing question. Recently, retinoid-related molecules, including 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3Cl-AHPC), were shown to bind to SHP and enhance apoptosis. We have examined whether 3Cl-AHPC acts as an agonist and increases SHP activity in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes and delineated the underlying mechanisms. Contrary to this expectation, micromolar concentrations of 3Cl-AHPC increased CYP7A1 expression but indirectly via p38 kinase signaling. Nanomolar concentrations, however, repressed CYP7A1 expression and decreased bile acid levels in HepG2 cells, and little repression was observed when SHP was down-regulated by small hairpin RNA. Mechanistic studies revealed that 3Cl-AHPC bound to SHP, increased the interaction of SHP with liver receptor homologue (LRH)-1, a hepatic activator for CYP7A1 and CYP8B1 genes, and with repressive cofactors, Brahma, mammalian Sin3a, and histone deacetylase-1, and, subsequently, increased the occupancy of SHP and these cofactors at the promoters. Mutation of Leu-100, predicted to contact 3Cl-AHPC within the SHP ligand binding pocket by molecular modeling, severely impaired the increased interaction with LRH-1, and repression of LRH-1 activity mediated by 3Cl-AHPC. 3Cl-AHPC repressed SHP metabolic target genes in a gene-specific manner in human primary hepatocytes and HepG2 cells. These data suggest that SHP may act as a ligand-regulated receptor in metabolic pathways. Modulation of SHP activity by synthetic ligands may be a useful therapeutic strategy.

/pdf/ligand-dependent-regulation-of-the-activity-of-the-orphan-3wetem4fzi.pdf

Ligand-Dependent Regulation of the Activity of the Orphan Nuclear Receptor, Small Heterodimer Partner (SHP), in the Repression of Bile Acid Biosynthetic CYP7A1 and CYP8B1 Genes

Lysosome‐mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor‐15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein‐B48 (ApoB48), the TG‐rich chylomicron marker, were elevated in SHP‐knockout and FGF15‐knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor‐EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding‐induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta‐mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19‐activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19‐SHP‐TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity‐associated metabolic disease.

Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut

Obesity-associated nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver failure and death. However, the pathogenesis of NAFLD and its severe form, nonalcoholic steatohepatitis (NASH), is poorly understood. The energy sensor, AMP-activated protein kinase (AMPK), has decreased activity in obesity and NAFLD, but the mechanisms are unclear. Here, we examined whether obesity-induced miR-802 has a role in promoting NASH by targeting AMPK. We also investigated whether miR-802 and AMPK have roles in modulating beneficial therapeutic effects mediated by obeticholic acid (OCA), a promising clinical agent for NASH.Immunoblotting, luciferase assays, and RNA-protein interaction studies were performed to test whether miR-802 directly targets AMPK. The roles of miR-802 and AMPK in NASH were examined in mice fed a NASH-promoting diet.Hepatic miR-802 and AMPK levels were inversely correlated in both NAFLD patients and obese mice. MicroRNA in silico analysis, together with biochemical studies in hepatic cells, suggested that miR-802 inhibits hepatic expression of AMPK by binding to the 3' untranslated regions of both human AMPKα1 and mouse Ampkβ1. In diet-induced NASH mice, OCA treatment reduced hepatic miR-802 levels and improved AMPK activity, ameliorating steatosis, inflammation, and apoptosis, but these OCA-mediated beneficial effects on NASH pathologies, particularly reducing apoptosis, were reversed by overexpression of miR-802 or downregulation of AMPK.These results indicate that miR-802 inhibits AMPK by directly targeting Ampkβ1, promoting NAFLD/NASH in mice. The miR-802-AMPK axis that modulates OCA-mediated beneficial effects on NASH may represent a new therapeutic target. 

https://doi.org/10.1016/j.molmet.2022.101603

Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice

ABSTRACT Macroautophagic/autophagic degradation of lipid droplets, lipophagy, is activated by fasting but repressed by feeding. Surprisingly, our recent study showed that this is not the case in the gut, where feeding activates lipophagy, reducing intestinal lipid levels. Transgenic mouse studies revealed that feeding activation of gut lipophagy requires both FGF15/FGF19 (fibroblast growth factor 15/fibroblast growth factor 19) and an orphan nuclear receptor, NR0B2/SHP (nuclear receptor subfamily 0, group B, member 2). Mechanistically, feeding-induced FGF15/FGF19 activates intestinal PRKC/PKC signaling, which in turn phosphorylates NR0B2 and the autophagic activator TFEB (transcription factor EB), leading to their nuclear localization and transcriptional induction of lipophagy network genes, including Ulk1 and Pnpla2/Atgl. Given that an essential function of the gut is to distribute dietary lipids throughout the body, this study identifies a physiologically important homeostatic mechanism to maintain healthy lipid levels. The intestinal FGF15/FGF19-NR0B2/SHP-TFEB pathway that regulates postprandial lipids by lipophagic activation, thus, may provide novel targets for treating dyslipidemia and obesity.

Sun Mi Seok

Papers

Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice

Ligand-Dependent Regulation of the Activity of the Orphan Nuclear Receptor, Small Heterodimer Partner (SHP), in the Repression of Bile Acid Biosynthetic CYP7A1 and CYP8B1 Genes

Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut

Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice

Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB