Our study provides the first direct evidence of role of SIBO and endotoxemia and its relation with TLR signaling genes and liver histology in patients with NAFLD.

We read with great interest the article by Cavazza et al., 1 who demonstrated that an advanced histological stage was the only risk factor associated with the development of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) from two European centers. Similar results were described in a Japanese multicenter study by Shibuya et al. 2 Although these studies suggest screening for HCC in patients with advanced-stage PBC, it is still uncertain whether there is a significantly increased risk of HCC development in patients with stage IV PBC cirrhosis versus patients with cirrhosis of other etiologies. We assessed in a single-center study the incidence of HCC in North American patients with stage IV PBC or autoimmune hepatitis (AIH) cirrhosis and compared it to the incidence of HCC in patients with hepatitis C virus (HCV) cirrhosis. Three hundred fifteen patients with HCV cirrhosis, 49 patients with AIH cirrhosis, and 52 patients with stage IV PBC were evaluated at the Cleveland Clinic between 2001 and 2007. Stage IV PBC cirrhosis was diagnosed when patients had positive serological and histological findings of cirrhosis or biochemical and radiological evidence of portal hypertension. Cirrhosis due to AIH was defined by positive serological and histological findings of cirrhosis or biochemical and radiological evidence of portal hypertension. HCC-free survival was analyzed from the moment of the diagnosis of cirrhosis in HCV, AIH, and PBC patients until death or transplantation. During a median follow-up of 3.6 years (with 25th and 75th percentiles of 1.8 and 6.3, respectively), 64 of 315 patients (20.3%) with HCV cirrhosis, 2 of 49 patients (4.1%) with AIH cirrhosis, and 4 of 52 patients (7.7%) with PBC cirrhosis developed HCC. The annual cumulative incidence of HCC was 1.1% in patients with AIH cirrhosis, 1.5% in patients with PBC cirrhosis, and 4.0% in patients with HCV cirrhosis (Fig. 1). This study has shown that although patients with stage IV PBC cirrhosis develop liver cancer, the risk is significantly lower in comparison with the risk for patients with HCV cirrhosis. The results of our study are discordant with a previously reported Spanish series in which the risks of HCC were similar in patients with late-stage PBC and in patients with HCV cirrhosis. 3 We agree with Cavazza et al. 1 that the low prevalence of PBC and the possible influence of geography on disease progression are confounding factors that may explain the divergent results in the literature. Future multicenter studies in North America with a longer follow-up period are necessary to validate these findings and better estimate the risk of HCC in PBC patients at an advanced histological stage.

Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.

Obesity results from increased energy intake or defects in energy expenditure. Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. Peroxisome proliferator–activated receptor γ coactivator 1α (PGC1α) controls BAT-mediated thermogenesis by regulating the expression of Ucp1. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays an important role in cell proliferation and differentiation. We demonstrate a novel function of Id1 in BAT thermogenesis and programming of beige adipocytes in white adipose tissue (WAT). We found that adipose tissue–specific overexpression of Id1 causes age-associated and high-fat diet–induced obesity in mice. Id1 suppresses BAT thermogenesis by binding to and suppressing PGC1α transcriptional activity. In WAT, Id1 is mainly localized in the stromal vascular fraction, where the adipose progenitor/precursors reside. Lack of Id1 increases beige gene and Ucp1 expression in the WAT in response to cold exposure. Furthermore, brown-like differentiation is increased in Id1-deficient mouse embryonic fibroblasts. At the molecular level, Id1 directly interacts with and suppresses Ebf2 transcriptional activity, leading to reduced expression of Prdm16, which determines beige/brown adipocyte cell fate. Overall, the study highlights the existence of novel regulatory mechanisms between Id1/PGC1α and Id1/Ebf2 in controlling brown fat metabolism, which has significant implications in the treatment of obesity and its associated diseases, such as diabetes.