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ObjectivePeroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).DesignWe constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.ResultsHepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing.ConclusionsAltogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.

Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria–xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions—germ-free or antibiotic-treated animals—as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual’s microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant-induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants.

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The Canarian Archipelago is a group of volcanic islands on a slow-moving oceanic plate, close to a continental margin. The origins of the archipelago are controversial: a hotspot or mantle plume, a zone of lithospheric deformation, a region of compressional block-faulting or a rupture propagating westwards from the active Atlas Mountains fold belt have been proposed by different authors. However, comparison of the Canarian Archipelago with the prototypical hotspot-related island group, the Hawaiian Archipelago, reveals that the differences between the two are not as great as had previously been supposed on the basis of older data. Quaternary igneous activity in the Canaries is concentrated at the western end of the archipelago, close to the present-day location of the inferred hotspot. This is the same relationship as seen in the Hawaiian and Cape Verde islands. The latter archipelago, associated with a well-defined but slow-moving mantle plume, shows anomalies in a plot of island age against distance which are comparable to those seen in the Canary Islands: these anomalies cannot therefore be used to argue against a hotspot origin for the Canaries. Individual islands in both archipelagoes are characterized by initial rapid growth (the ‘shield-building’ stages of activity), followed by a period of quiescence and deep erosion (erosion gap) which in turn is followed by a ‘post-erosional’ stage of activity. The absence of post-shield stage subsidence in the Canaries is in marked contrast with the major subsidence experienced by the Hawaiian Islands, but is comparable with the lack of subsidence evident in other island groups at slow-moving hotspots, such as the Cape Verdes. Comparison of the structure and structural evolution of the Canary Islands with other oceanic islands such as Hawaii and Réunion reveals many similarities. These include the development of triple (‘Mercedes Star’) rift zones and the occurrence of giant lateral collapses on the flanks of these rift zones. The apparent absence of these features in the post-erosional islands may in part be a result of their greater age and deeper erosion, which has removed much of the evidence for their early volcanic architecture. We conclude that the many similarities between the Canary Islands and island groups whose hotspot origins are undisputed show that the Canaries have been produced in the same way.

During the Pleistocene, east of Lago Buenos Aires, Argentina, at 46.5 ؇S, at least 19 terminal moraines were deposited as piedmont glaciers from the Patagonian ice cap advanced onto the semi-arid high plains adjacent to the southern Andes. Exceptional preservation of these deposits offers a rare opportunity to document ice-cap fluctuations during the last 1.2 m.y. 40 Ar/ 39 Ar incremental-heating and unspiked K-Ar experiments on four basaltic lava flows interbedded with the moraines provide a chronologic framework for the entire glacial sequence. The 40 Ar/ 39 Ar isochron ages of three lavas that overlie till 90 km east of the Cordillera at Lago Buenos Aires, and another 120 km from the Andes along Río Gallegos at 51.8 ؇S that underlies till, strongly suggest that the ice cap reached its greatest eastward extent ca. 1100 ka. At least six moraines were deposited within the 256 k.y. period bracketed by basaltic eruptions at 1016 ؎ 10 ka and 760 ؎ 14 ka. Similarly, six younger, more proximal moraines were deposited during an ϳ651 k.y. period bracketed by an underlying 760 ؎ 14 ka basalt and the 109 ؎ 3 ka Cerro Volcán basalt flow that buried all six moraines. Coupled with in situ cosmogenic surface exposure ages of moraine boulders, the 109 ka age of Cerro Volcán implies that moraines deposited during the penultimate local glaciation correspond to marine oxygen

The Teide and Pico Viejo stratocones and the Northwest and Northeast Rifts are products of the latest eruptive phase of the island of Tenerife, initiated with the lateral collapse of its northern fl ank that formed the Las Cañadas Caldera and the Icod-La Guancha Valley ca. 200 ka. The eruptive and structural evolution of this volcanic complex has been reconstructed after detailed geological mapping and radioisotopic dating of the signifi cant eruptive events. A set of 54 new 14 C and K/Ar ages provides precise age control of the recent eruptive history of Tenerife, particularly Teide Volcano, the third-highest volcanic feature on Earth (3718 m above sea level, >7 km high), and unique in terms of its intraplate setting. The development of the Teide-Pico Viejo Volcanoes may be related to the activity of the Northwest and Northeast Rifts. Volcanic and intrusive activity along both rift zones may have played an important role in activating the gravitational landslide and in the subsequent growth, nested within the collapse embayment, of an increasingly higher central volcano with progressively differentiated magmas. The coeval growth of the central volcano with sustained activity along the rifts led to a clear bimodal distribution in composition of eruptive products, with the basaltic eruptions in the distal part of the rifts and phonolitic and more explosive eruptions in the central area, where the differentiated stratocones developed. Current volcanic hazard in Tenerife is considered to be moderate, because eruptive frequency is low, explosivity is modest, and the eruptive activity of the Teide stratocone seems to have declined over the past 30 k.y., with only one eruption in this period (1150 yr B.P.).