The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of ...vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.
Liver X receptors (LXRs) are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. Under normal conditions, when ...intracellular cholesterol concentration increases, cells synthesize oxysterols and activate the LXR transcriptional network to drive cholesterol efflux and reduce cholesterol influx and synthesis. During normal and cancer cell proliferation, there is a net uncoupling between intracellular cholesterol increase and LXR activation resulting from the reduced intracellular oxysterol concentration. This review dissects the novel mechanisms of a previously unrecognized metabolic uncoupling, supporting the activation of the LXR axis as a bona fide therapeutic approach in cancer.
Bovenga et al. review how intracellular cholesterol levels and activation of the nuclear receptor LXR can be uncoupled during cell proliferation and discuss the therapeutic potential of targeting cancer cell metabolism via pharmacological modulation of LXR activity.
Western populations are becoming increasingly sedentary and the incidence of nonalcoholic fatty liver disease (NAFLD) is increasing and becoming one of the most common causes of liver disease ...worldwide. Also, NAFLD is considered one the new emerging risk factors for development of tumors of the gastro-intestinal tract, particularly hepatocellular carcinoma (HCC). Visceral obesity is an important risk factor for the onset of NAFLD. An accumulation of ectopic fat, including visceral obesity and fatty liver leads to a dysfunction of the adipose tissue with impaired production of adipocytokines which, in turn, favor an increase in pro-inflammatory cytokines. In this review, we discuss how the obesity-related chronic state of low-grade inflammation and the presence of NAFLD lead to the emergence of a microenvironment favorable to the development of cancer.
Abstract
Visceral obesity is characterized by a low-grade inflammatory systemic state that contributes to the genesis of non-alcoholic fatty liver disease (NAFLD), frequently associated with liver ...fibrosis. Non-invasive serum markers have recently emerged as reliable, easy-to-use scores to predict liver fibrosis. NAFLD is often linked to metabolic and cardiovascular risk. Thus, in this cross-sectional study, we investigated in a population of 1225 subjects if AST to Platelet Ratio Index (APRI), one of the non-invasive liver fibrosis serum markers, can predict cardiovascular risk (CVR). APRI has been previously validated as an efficient score to predict liver fibrosis in viral hepatitis patients with a cut-off of 0.5 for fibrosis and 1.5 for cirrhosis. Our study showed that APRI significantly correlates with CVR and determines, when elevated, a significant increase in CVR for both genders, especially females. This spike in CVR, observed when APRI is elevated, is relatively high in patients in the age of 51–65 years, but it is significantly higher in younger and premenopausal women, approaching risk values usually typical of men at the same age. Taken together, our data highlighted the role of APRI as a reliable predictor easy-to-use score for CVR in metabolic patients.
Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of ...metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.
Edible plants are gaining importance as an integrative therapy for many chronic diseases, including cancer. We first reported that the edible wild plant
Crithmum maritimum
L. inhibits the growth of ...hepatocellular carcinoma (HCC) cells by exerting a multitarget action on cellular metabolism and bioenergetic profile. Here, we show that
Crithmum maritimum
ethyl acetate extract significantly increases the responsiveness of HCC cells to the chemotherapeutic drug sorafenib by reducing lactic acid fermentation and inducing a pro-hepatocyte biomarker profile. Our findings strengthen the role of
Crithmum maritimum
L. as a valuable nutraceutical tool to support pharmacological therapeutic interventions in HCC.
In the past few years, evidence has supported the role of plants as a valuable tool for the development of promising therapeutic support options for many diseases, including cancer. We recently ...discovered that the edible wild plant
Crithmum maritimum
L. effectively inhibits the growth of hepatocellular carcinoma (HCC) cells and we provide insights into the biological mechanisms involved. Here, we aimed to characterize the effect of ethyl acetate extract of
Crithmum maritimum
on the bioenergetic phenotype of HCC cells and if this is associated with the anti-tumour effect we previously described. Results show that
Crithmum maritimum
significantly increases cellular respiration and reduces lactic fermentation in HCC cells, and that this reduction of the fermentative glycolytic phenotype is linked to inhibition of HCC growth. These data provide new preclinical evidence supporting the role of
Crithmum maritimum
L. as a nutraceutical option to expand the therapeutic opportunities in the management of HCC.
The Association of hereditary hemorrhagic telangiectasia (HHT) and type I hereditary angioedema is a very rare condition in medicine. The case reported by Muller et al., describes the coexistence of ...the two diseases and emphasizes the need for listing HHT patients for liver transplantation in case indications occurs, such as the presence of HCC, abnormally increased cardiac output, and gastrointestinal bleeding as reported for this case. The case described by Mueller et al. is anecdotal for the usefulness of liver transplantation in HHT patients and shows that liver transplantation may be the best supportive care and, sometimes, the unique and final therapeutic option for these patients.
Abstract
Hepatocellular carcinoma (HCC) is nowadays the sixth cause of tumour-related deceases worldwide, estimated to become the third in Western countries by 2030. New drugs for HCC treatment still ...have many adverse effects. Several lines of evidence indicate that plant metabolites offer concrete opportunities for developing new therapeutic strategies for many diseases, including cancer. We previously reported that ethyl acetate extract of a spontaneous edible plant harvested in Apulia,
Crithmum maritimum
, significantly inhibited cell growth in HCC cells. By
1
H-NMR spectroscopy, here we show that
Crithmum maritimum
ethyl acetate extract counteracts the Warburg effect, by reducing intracellular lactate, inhibits protein anabolism, by decreasing amino acid level, and affects membrane biosynthesis by lowering choline and phosphocholine. Also, we observed an effect on lipid homeostasis, with a reduction in triglycerides, cholesterol, monounsaturated fatty acids (MUFA), and diunsaturated fatty acids (DUFA), and an increase in polyunsaturated fatty acids (PUFA). Taken together, these data demonstrate that
Crithmum maritimum
-induced cytostasis is exerted through a multi-effect action, targeting key metabolic processes in HCC cells. Overall, our findings highlight the role of
Crithmum maritimum
as a promising tool for the prevention and the improvement of the therapeutic options for HCC and other types of tumours.
Despite the reducing incidence of chronic hepatitis infections, an unexpected increasing incidence of hepatocellular carcinoma (HCC) has being occurred. This may be explained by the increasing number ...of HCCs developing on steatosis (NAFLD) and steatohepatitis (NASH), related to metabolic risk factors (i.e. diabetes mellitus type II, obesity, metabolic syndrome), which are becoming emerging risk factors for HCC. This led to a growing scientific interest on the oncogenic mechanisms underlying the transition from NAFLD to HCC. However, patients with NASH receive significantly less HCC surveillance than patients with chronic hepatitis, and no specific preventive pharmacological treatments have recommended for NASH-related HCC. This review focuses on the pathogenic role of the emerging factors involved in the transition from NAFLD/NASH to HCC, including microbiota, insulin resistance, inflammation, lipid and bile acids metabolism. It will be emphasize their impact on the liver microenvironment, the implications in clinical practice and the future directions of research.
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•Increasing incidence of HCC related to metabolic conditions (i.e. NAFLD and NASH)•Oncogenic mechanisms underlying the transition from NAFLD/NASH to HCC•Less HCC surveillance in patients with NASH versus those with chronic hepatitis•Metabolic factors and hepatic microenvironment in the transition from NASH to HCC
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