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Background: Kruppel like factor 6 (KLF6) is a zinc finger transcription factor and candidate tumour suppressor first identified as an immediate early gene in injured hepatic stellate cells (HSC). It also upregulated in association with oxidative stress and increased TGFbetal levels in animals with steatohepatitis induced by a methionine-choline deficient (MCD) diet and is a proposed mediator of progressive inflammation and fibrosis. We have recently identified a KLF6 polymorphism (KLF6-IVS I-27G >A) associated with alternative splicing to dominant negative KLF6 isoforms and an increased incidence of familial prostate cancer. The aim of this study was to assess the prevalence of KLF6-1VS1-27G > A in patients with NAFLD. Patients and Methods: We enrolled 3 12 Caucasian patients with NAFLD. Grading and staging of steatosis, inflammation and fibrosis were as defined by Brunt. A 290 base pair amplicon was generated from peripheral blood DNA using primers spanning the SNP in KLF6 intron 1. The enzyme BsaA I cuts at the ‘CGCG’ of the wild type sequence. Results: The frequency of KLF6-IVS1-27G > A (rs3750861 I ) was 15% in a European population studied in the International HapMap project. The G > A allele was similarly present in 451312 (14.4%) of our patients with NAFLD. However, when considering patients with minimal versus advenced fibrosis the incidence was 18% versus 8%. As a group, the KLF6 heterozygotes had significantly less advanced fibrosis (p 0.05), with 76% having stage 0 or 1 disease, versus 57% of wt individuals. The odds ratio for development of advanced fibrosis in KLF6 wt versus heterozygous individuals was 2.4 [CI 0.93-4.31. Discussion: Induction of KLF6 expression in HSC in response to liver injury contributes to their activation. Induction associated with an increased ratio of dominant negative KLF6 splice forms, sequestering KLF6 in the cytoplasm, may well inhibit this and subsequent pro-fibrogenic processes. In view of the recently postulated link between hepatocyte senescence and fibrosis, it is also possible that KLF6-IVS I-27G > A impedes progressive disease by facilitating hepatocyte regeneration in the face of chronic injury. A polymorphism associated with more rapid tumour growth and familial cancers may therefore have beneficial effects in promoting cell survival in a non-cancer, chronic disease situation.

In 1863, Landois showed that infusion of bile into animals could produce a negative chronotropic effect [1]. This has since been attributed to raised concentrations of bile acids [2.3], however, recent reports of «digoxin-like activity» in both normal bile [4] and the serum of patients with liver disease [5-11] suggest an alternative explanation

Nonalcoholic fatty liver disease (NAFLD) defines the most of common liver diseases encompassing alcohol-like hepatic histologic lesions seen in the non-alcoholic insulin resistant patient. NAFLD, deemed to be the hepatic counterpart of the metabolic syndrome, represents a multifactorial condition spanning the widespectrum from steatosis through non-alcoholic steatohepatitis (NASH) with or without (cryptogenic) cirrhosis. End-stage liver failure and hepatocellular carcinoma are observed in a yet undetermined proportion of individuals. Along with insulin resistance, additional endocrine and vascular changes play a prominent role in the development and progression of NAFLD. Genetic factors underlying NAFLD are being unravelled. Their understanding will further our understanding of pathogenesis and will also probably enhance non-invasive diagnosis. Diet and physical exercise represent, with the correction of predisposing metabolic changes, the mainstay of treatment. Insulin sensitizing drugs should better be used only in selected patients, preferably in the context of controlled clinical trials. Non-invasive evaluation of risk for cardiovascular events is recommended in all individuals presenting with NAFLD and conversely, the presence of NAFLD should be always looked for in subjects with features belonging to the metabolic syndrome.