Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. ...This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.
Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options ...are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.
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•WAT browning contributes to high energy expenditure in cancer-associated cachexia•Systemic inflammation and IL-6 induce and sustain WAT browning in cachexia•Inhibition of WAT browning ameliorates the severity of cachexia•Cancer cachexia patients stain positive for UCP1 protein in WAT
Cancer-associated cachexia is a wasting syndrome responsible for morbidity and mortality in many cancer patients with advanced disease. Petruzzelli et al. show that inflammation-mediated browning of white adipose tissue is a consistent early feature of cachexia. Moreover, positive staining for UCP1 was observed in adipose tissue from cancer cachexia patient samples, suggesting that increased adipose thermogenesis is also a feature of human cancer.
Background & Aims Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor ...(FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BAs and protecting the liver from cholestasis in mice. Methods We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-of-function models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. Results Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BAs and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis after bile duct ligation or administration of α-naphthylisothiocyanate. In Mdr2 −/− mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. Conclusions Activation of FXR transcription in the intestine protects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients.
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.
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► Intestinal-specific LXR activation increases preβ-HDL cholesterol and induces RCT ► Hepatic-specific LXR activation does not contribute to RCT ► Intestinal-specific LXR activation prevents diet-induced hepatic lipogenesis and fatty liver ► Intestinal-specific LXR activation protects from atherosclerosis in the LDLR−/− mice
An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of ...colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
Bile formation springs from an extraordinary sophisticated secretory network, which combines the activity of transport proteins with the physico-chemical properties of small albeit powerful ...lipophilic compounds. This robust interplay is activated in response to dietary stimuli, circadian rhythms, and metabolic demands to regulate cholesterol disposal, lipid digestion and absorption in the enterohepatic system. As a result, bile flow is a complex multi-organ effort that requires an integrated flux of information between liver and intestine. A coordinate regulatory task is achieved by nuclear receptors, which are ligand activated transcription factors, responsible for the coherent activation of sets of genes involved in multiple physiological actions, including hepato-biliary homeostasis. Mastering the molecular pathways underlying functional and pharmacological modulation of bile flow has great translational value for potential future treatment of cholestasis and cholelithiasis. In this review, we focus on recent discoveries in the functional biology of bile formation with the explicit aim of underlining their putative clinical relevance.
The metabolic syndrome is an emerging global epidemic characterized by clustering of metabolic abnormalities leading to increased cardiovascular risk: glucose intolerance or type 2 diabetes, ...dyslipidemia, hypertension, and "central" obesity. Scientists are decoding and piecing together the molecular texture underlying the metabolic syndrome: insulin resistance and dyslipidemia stand out as central pathophysiological events. In this picture, the liver rises as the leading organ in the maintenance of metabolic fitness; it serves as the first relay station for processing dietary information, and encloses the whole biochemical machinery for both glucose and lipid storage and disposal. In addition, the liver is a target of the different endocrine molecules secreted by pancreatic beta-cells and adipose tissue. Evidence collected in animal models supports the central role of the liver in the metabolic syndrome. While specific bereft of insulin sensitivity in skeletal muscle and adipose tissue fails to induce diabetes at certain extent, this is constantly the outcome in case of hepatic insulin resistance. Also, dyslipidemia is currently interpreted as the result of increased flux of free fatty acids to the liver with ensuing misbalance of lipoprotein synthesis and removal. In this review we bring together recent advances in the field of lipid sensing nuclear receptors, adipokines and other molecules responsible for metabolic fitness, and provide a putative coherent frame to conceive the pathophysiology of the metabolic syndrome.
The strong analgesic, anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) are hampered by high occurrence of gastrointestinal side effects. Therapeutic actions of NSAIDs ...result from cyclooxygenase (COX) enzymes inhibition with reduced synthesis of prostaglandins, major modulators of inflammation. Since prostaglandins also regulate key events in gut homeostasis –mucosal secretion, blood flow, epithelial regeneration – COX inhibition has been accepted as the reason for NSAID gastrointestinal toxicity. Several findings challenge this theory: first, intestinal damage by NSAIDs occurs also in COX-1 knockout mice, demonstrating that topical (non-prostaglandin mediated) mechanisms are involved; second, no correlation is found
in vivo between the extent of intestinal injury and the degree of inhibition of prostaglandin synthesis; third, bile flow interruption in animal models completely prevents intestinal damage by parenterally administered NSAIDs. What is in bile that could play a role in NSAID toxicity? This timely review will critically discuss the role of bile salts in NSAID-dependent gut damage.
Nutritional and genetic factors alter the intestinal microflora, predisposing individuals toward metabolic syndrome. Gewirtz and coworkers (
Vijay-Kumar et al., 2010), employing Toll-like receptor 5 ...null mice, present evidence for a direct relationship between malfunction of the innate immune system, changes in gut microbiota composition, and development of metabolic syndrome.
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