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  • br Conclusions and future directions of research NASH relate


    Conclusions and future directions of research NASH-related cirrhotic patients receive significantly less surveillance for HCC than those with HCV-related cirrhosis [98]. As a matter of fact, this is strongly in Tadalafil with epidemiological data and represents a considerable problem of public health. In fact, prevention is the first intervention to invert the increasing incidence of HCC. However, cancer prevention primarily requires the correct identification of the “new patients at higher risk for HCC”. Therefore, to early diagnose hepatic steatosis, personalized screening programs should be implemented in patients with diabetes mellitus, obesity and metabolic syndrome. Further studies are necessary to better disclose hepatic histological changes with noninvasive measures such as serum biomarkers for reducing the need of biopsies for diagnosis of NASH. In the absence of fibrosis or NASH, pharmacological interventions are not recommended and a combined lifestyle approach, including low caloric intake with specific nutrients composition, and physical activity is still considered the most effective preventive intervention in liver steatosis. Pioglitazone and vitamin E are the only preventive treatments recommended in patients with NASH by EASL and AASLD guidelines, despite there is no complete information on their long-term safety and efficacy [51]. Other therapies (i.e. statins, antidiabetics, etc.) may be used in NAFLD/NASH at high CVD or HCC risk, but with the main indication of cardiovascular prevention. Considering the strong crosstalk between the emerging metabolic factors and liver microenvironment, a wide variety of drugs targeting the underlying pathophysiological mechanisms (i.e. inflammation, IR, adipokine imbalance, SIBO, lipid and BAs metabolism) have been proposed as cancer prevention in NASH. However, there is little evidence of any improvement or regression of liver necroinflammation and fibrosis [99]. Therefore, as recommended by US FDA, further long-duration trials are necessary to better evaluate drug efficacy in NASH patients, considering improvement of histological patterns as a primary endpoint [100].
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    Acknowledgments The work was supported by AIRC (Italian Association for Cancer Research) Investigator Grant (IG) 2015 Id.17758 (to A. Mazzocca).
    Introduction Insulin sensitivity is critical for glucose homeostasis. The pleiotropic actions of insulin in tissues are initiated by binding of insulin to the insulin receptor (IR), which consists of two subunits, IRα and IRβ. The activated insulin receptors are autophosphorylated and subsequently recruit and phosphorylate the insulin receptor substrates (IRSs), which initiates an insulin signaling cascade that culminates in the phosphorylation of AKT kinases [1], [2], [3]. Once activated, AKT kinases affect at least two important downstream pathways, which may also tissue dependent, to modulate glucose homeostasis. One pathway involves phosphorylation and inactivation of glycogen synthase kinase 3β (GSK3β), resulting in glycogen synthase activation and glycogen accumulation; another pathway involves phosphorylation and inactivation of FOXO1 (forkhead box class O family member protein 1), which regulates transcription of genes encoding gluconeogenic enzymes [4]. Under insulin resistance, tissues fail to respond to physiological level of insulin, leading to compensatory hyperinsulinemia, a principal feature of type 2 diabetes and other metabolic diseases [5], [6], [7]. The insulin receptor serves crucial roles in directing insulin to specific target tissues and initiating the downstream insulin signaling, Tadalafil thus, insulin receptor dysfunction leads to defective transmembrane signaling, insulin resistance and type 2 diabetes [8]. In insulin-resistant individuals, reduced/absent insulin receptor expression has been found [8]. It has been reported that a nucleoprotein complex, consisted of high mobility group AT-hook 1 (HMGA1), C/EBPβ and Sp1, regulates the transcription of INSR, the gene encoding IRα and IRβ [9]. HMGA1 is an important nuclear factor responsible for gene activation [10], [11], and deficiency of HMGA1 causes insulin resistance and diabetes in human and mice through impairing the transcription of INSR [10]. On the other hand, insulin induces HMGA1 phosphorylation and represses its associated gene transcription, including insulin-like growth factor-binding protein-1 (IGFBP-1) and INSR genes [12]. Therefore, HMGA1 not only acts as a regulator, but also as a sensor, of insulin signaling.