In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice.

Background: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation. Methods: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXR null mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis. Findings: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR) null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease. Interpretation: Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.

Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4−/− and Fxr−/− mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4−/− and Fxr−/− mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.

The present data elect hepatic PGC-1β as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. (Hepatology 2018;67:884-898).

Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr−/− and Abcb4−/− mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr−/− mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro-inflammatory cytokines. Moreover, in Abcb4−/− mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC.

Several studies highlighted the importance of platelets in the tumor microenvironment due to their ability to interact with other cell types such as leukocytes, endothelial, stromal and cancer cells. Platelets can influence tumor development and metastasis formation through several processes consisting of the secretion of growth factors and cytokines and/or via direct interaction with cancer cells and endothelium. Patients with visceral obesity (VO) are susceptible to pro-thrombotic and pro-inflammatory states and to development of cancer, especially colon cancer. These findings provide us with the impetus to analyze the role of platelets isolated from VO patients in tumor growth and progression with the aim to explore a possible link between platelet activation, obesity and colon cancer. Here, using xenograft colon cancer models, we prove that platelets from patients with visceral obesity are able to strongly promote colon cancer growth. Then, sequencing platelet miRNome, we identify miR-19a as the highest expressed miRNA in obese subjects and prove that miR-19a is induced in colon cancer. Last, administration of miR-19a per se in the xenograft colon cancer model is able to promote colon cancer growth. We thus elect platelets with their specific miRNA abundance as important factors in the tumor promoting microenvironment of patients with visceral obesity.

The proliferative-crypt compartment of the intestinal epithelium is enriched in phospholipids and accumulation of phospholipids has been described in colorectal tumors. Here we hypothesize that biliary phospholipid flow could directly contribute to the proliferative power of normal and dysplastic enterocytes. We used Abcb4−/− mice which lack biliary phospholipid secretion. We first show that Abcb4−/− mice are protected against intestinal tumorigenesis. At the molecular level, the transcriptional activity of the nuclear receptor Liver Receptor Homolog-1 (Lrh1) is reduced in Abcb4−/− mice and its re-activation re-establishes a tumor burden comparable to control mice. Feeding Abcb4−/− mice a diet supplemented with phospholipids completely overcomes the intestinal tumor protective phenotype, thus corroborating the hypothesis that the absence of biliary phospholipids and not lack of Abcb4 gene per se is responsible for the protection. In turn, phospholipids cannot re-establish intestinal tumorigenesis in Abcb4−/− mice crossed with mice with intestinal specific ablation of Lrh1, a nuclear hormone receptor that is activates by phospholipids. Our data identify the key role of biliary phospholipids in sustaining intestinal mucosa proliferation and tumor progression through the activation of nuclear receptor Lrh1.

Acetaminophen (APAP) is a worldwide commonly used painkiller drug. However, high doses of APAP can lead to acute hepatic failure and, in some cases, death. Previous studies indicated that different factors, including life-style and metabolic diseases, could predispose to the risk of APAP-induced liver failure. However, the molecular process that could favor APAP hepatotoxicity remains understood. Here, we reported that a short-term high fat-enriched diet worsens APAP-induced liver damage, by promoting liver accumulation of lipids that induces the activation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β). Therefore, we challenged mice with hepatic-specific PGC-1β overexpression on a chow diet with a subtoxic dose of APAP and we found that PGC-1β overexpression renders the liver more sensitive to APAP damage, mainly due to intense oxidative stress, finally ending up with liver necrosis and mice death. Overall, our results indicated that during high fat feeding, PGC-1β adversely influences the ability of the liver to overcome APAP toxicity by orchestrating different metabolic pathways that finally lead to fatal outcome.