The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

The G protein-coupled receptor TGR5 has been identified as an important component of the bile acid signaling network, and its activation has been linked to enhanced energy expenditure and improved glycemic control. Here, we demonstrate that activation of TGR5 in macrophages by 6α-ethyl-23(S)-methylcholic acid (6-EMCA, INT-777), a semisynthetic BA, inhibits proinflammatory cytokine production, an effect mediated by TGR5-induced cAMP signaling and subsequent NF-κB inhibition. TGR5 activation attenuated atherosclerosis in Ldlr(-/-)Tgr5(+/+) mice but not in Ldlr(-/-)Tgr5(-/-) double-knockout mice. The inhibition of lesion formation was associated with decreased intraplaque inflammation and less plaque macrophage content. Furthermore, Ldlr(-/-) animals transplanted with Tgr5(-/-) bone marrow did not show an inhibition of atherosclerosis by INT-777, further establishing an important role of leukocytes in INT-777-mediated inhibition of vascular lesion formation. Taken together, these data attribute a significant immune modulating function to TGR5 activation in the prevention of atherosclerosis, an important facet of the metabolic syndrome.

The nuclear receptor REV-ERBα shapes the daily activity profile of Sterol Response Element Binding Protein (SREBP) and thereby participates in the circadian control of cholesterol and bile acid synthesis in the liver.

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.

Several steps of the HDL-mediated reverse cholesterol transport (RCT) are transcriptionally regulated by the nuclear receptors LXRs in the macrophages, liver, and intestine. Systemic LXR activation via synthetic ligands induces RCT but also causes increased hepatic fatty acid synthesis and steatosis, limiting the potential therapeutic use of LXR agonists. During the last few years, the participation of the intestine in the control of RCT has appeared more evident. Here we show that while hepatic-specific LXR activation does not contribute to RCT, intestinal-specific LXR activation leads to decreased intestinal cholesterol absorption, improved lipoprotein profile, and increased RCT in vivo in the absence of hepatic steatosis. These events protect against atherosclerosis in the background of the LDLR-deficient mice. Our study fully characterizes the molecular and metabolic scenario that elects the intestine as a key player in the LXR-driven protective environment against cardiovascular disease.

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38a activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38a sustains the expression of HIF1a target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38a triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38a inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc Min mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38a affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs. Colorectal cancer is the second leading cause of death for tumors in the western world because of a high percentage of metastatic disease, which shows a 5-year survival rate of approximately 10%.

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid β-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1α drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-offunction genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1α regulates enterocyte cell fate and protects against tumorigenesis.colon cancer | medical physiology | metabolism | mitochondria | nuclear receptors