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Several laboratories, including ours, have employed the Slc25a47 tm1c(EUCOMM)Hmgu mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1 , the cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses. [Display omitted] • Downregulation of WARS1 in hepatocytes triggers a hypermetabolic phenotype. • Reduced WARS1 expression leads to significant liver damage and fibrosis. • WARS1 downregulation triggers ISR and disrupts mitochondrial translation, inducing UPRmt. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels. [Display omitted] • Multi-omics data and bile acid profiles were collected from ∼360 male BXD mice • Bile acid levels are strongly influenced by genetics and environment • Numerous genetic loci associate to bile acid abundance • CES1C is identified as a modulator for tauroursodeoxycholic acid plasma abundance Li et al. use the BXD mouse reference population to evaluate how genetics and diet regulate bile acid homeostasis. Through this integrated systems genetics approach, they mapped hundreds of genetic loci associated with bile acids and identified carboxylesterase 1C as a modulator for tauroursodeoxycholic acid plasma abundance. [ABSTRACT FROM AUTHOR]

In the past decade substantial progress has been made in understanding how the insurgence of chronic low-grade inflammation influences the physiology of several metabolic diseases. Tissue-resident immune cells have been identified as central players in these processes, linking inflammation to metabolism. The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages, and its activation mediates potent anti-inflammatory effects. Herein, we summarize recent advances in TGR5 research, focusing on the downstream effector pathways that are modulated by TGR5 activators, and on its therapeutic potential in inflammatory and metabolic diseases. [ABSTRACT FROM AUTHOR]

Summary Mitochondrial activity is controlled by proteins encoded by both nuclear and mitochondrial DNA. Here, we identify Sirt7 as a crucial regulator of mitochondrial homeostasis. Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction, which is reflected by increased blood lactate levels, reduced exercise performance, cardiac dysfunction, hepatic microvesicular steatosis, and age-related hearing loss. This link between SIRT7 and mitochondrial function is translatable in humans, where SIRT7 overexpression rescues the mitochondrial functional defect in fibroblasts with a mutation in NDUFSI . These wide-ranging effects of SIRT7 on mitochondrial homeostasis are the consequence of the deacetylation of distinct lysine residues located in the hetero- and homodimerization domains of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes. SIRT7-mediated deacetylation of GABPβ1 facilitates complex formation with GABPα and the transcriptional activation of the GABPα/GABPβ heterotetramer. Altogether, these data suggest that SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function. [ABSTRACT FROM AUTHOR]

Summary Reverse cholesterol transport (RCT) is an antiatherogenic process in which excessive cholesterol from peripheral tissues is transported to the liver and finally excreted from the body via the bile. The nuclear receptor liver receptor homolog 1 (LRH-1) drives expression of genes regulating RCT, and its activity can be modified by different posttranslational modifications. Here, we show that atherosclerosis-prone mice carrying a mutation that abolishes SUMOylation of LRH-1 on K289R develop less aortic plaques than control littermates when exposed to a high-cholesterol diet. The mechanism underlying this atheroprotection involves an increase in RCT and its associated hepatic genes and is secondary to a compromised interaction of LRH-1 K289R with the corepressor prospero homeobox protein 1 (PROX1). Our study reveals that the SUMOylation status of a single nuclear receptor lysine residue can impact the development of a complex metabolic disease such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Class IB phosphoinositide 3-kinase p110γ is a master regulator of both leukocyte and cardiomyocyte function. Whereas in the immune system p110γ is principally involved in the control of leukocyte chemotaxis and inflammatory reactions, in cardiomyocytes p110γ affects multiple aspects of β-adrenergic receptor signaling and cardiac function. Because inflammatory cell recruitment/activation and cardiac dysfunction are strictly connected, p110γ has recently been revealed as a promising target for drug design in the treatment of heart failure. This review discusses recent works that dissect the relative contribution of leukocyte p110γ and its cardiac counterpart in the onset and progression of pressure overload–induced cardiac remodeling and the ensuing therapeutic implications. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity. [Display omitted] • Diet-induced obesity induces changes in the hypothalamic BA-TGR5 system • Central TGR5 agonism reduces obesity by activating the sympathetic nervous system • Hypothalamic TGR5 protects from the onset and worsening of diet-induced obesity • Hypothalamic TGR5 participates in the anti-obesity effects of BA supplementation Castellanos-Jankiewicz et al. demonstrate that activation of central TGR5 signaling counteracts diet-induced obesity, whereas genetic downregulation of hypothalamic TGR5 promotes it. These effects involve modulation of food intake and energy expenditure through the sympathetic nervous system, revealing a long-range bile acid-dependent hypothalamic mechanism contributing to weight regulation in obesity. [ABSTRACT FROM AUTHOR]

Bile acid metabolism is tightly controlled due to the toxic effects of bile acid overload. In this issue, research from the Feng lab reports Shp2 as a novel integrator of hepatic bile acid and FGF15/FGF19 signaling, adding another layer of complexity to the control of bile acid biosynthesis. [ABSTRACT FROM AUTHOR]

Renewal and patterning of the intestinal epithelium is coordinated by intestinal stem cells (ISCs); dietary and metabolic factors provide signals to the niche that control ISC activity. Bile acids (BAs), metabolites in the gut, signal nutrient availability by activating the G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5). TGR5 is expressed in the intestinal epithelium, but it is not clear how its activation affects ISCs and regeneration of the intestinal epithelium. We studied the role of BAs and TGR5 in intestinal renewal, and regulation of ISC function in mice and intestinal organoids. We derived intestinal organoids from wild-type mice and Tgr5 –/– mice, incubated them with BAs or the TGR5 agonist INT-777, and monitored ISC function by morphologic analyses and colony-forming assays. We disrupted Tgr5 specifically in Lgr5 -positive ISCs in mice (Tgr5 ISC–/– mice) and analyzed ISC number, proliferation, and differentiation by flow cytometry, immunofluorescence, and organoid assays. Tgr5 ISC–/– mice were given cholecystokinin; we measured the effects of BA release into the intestinal lumen and on cell renewal. We induced colitis in Tgr5 ISC–/– mice by administration of dextran sulfate sodium; disease severity was determined based on body weight, colon length, and histopathology analysis of colon biopsies. BAs and TGR5 agonists promoted growth of intestinal organoids. Administration of cholecystokinin to mice resulted in acute release of BAs into the intestinal lumen and increased proliferation of the intestinal epithelium. BAs and Tgr5 expression in ISCs were required for homeostatic intestinal epithelial renewal and fate specification, and for regeneration after colitis induction. Tgr5 ISC–/– mice developed more severe colitis than mice without Tgr5 disruption in ISCs. ISCs incubated with INT-777 increased activation of yes-associated protein 1 (YAP1) and of its upstream regulator SRC. Inhibitors of YAP1 and SRC prevented organoid growth induced by TGR5 activation. BAs promote regeneration of the intestinal epithelium via activation of TGR5 in ISCs, resulting in activation of SRC and YAP and activation of their target genes. Release of endogenous BAs in the intestinal lumen is sufficient to promote ISC renewal and drives regeneration in response to injury. [ABSTRACT FROM AUTHOR]

Background Renin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function. Objectives This study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation. Methods We generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding. Results Chronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II–stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca 2+ uptake in transgenic mice, increased the Ca 2+ transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding–induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice. Conclusions We identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca 2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation. [ABSTRACT FROM AUTHOR]

Class I phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes involved in signal transduction triggered by growth factors and G-protein-coupled receptors. The catalytic function of PI3Ks is well known to promote a wide variety of biological processes, including proliferation, survival and migration, but a new layer of complexity in the function of PI3Ks has recently emerged, indicating that these proteins function not only as kinases but also as scaffold proteins. Knockout mice that lack PI3K protein expression show a different phenotype from knock-in mice expressing PI3K mutants that have lost their kinase activity, providing evidence for this novel role of PI3Ks. We will discuss such findings, highlighting the crucial scaffold function of PI3Kγ in cAMP homeostasis and PI3Kβ in receptor recycling. [Copyright &y& Elsevier]