DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH

Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH.

Treatment of NASH with ursodeoxycholic acid: cons

Non-alcoholic steatohepatitis (NASH) has a prevalence of 1% in Western countries. Its causes as well as its medical treatment are, to date, still debated. Recently, studies of agents suggested to have antiapoptotic, insulin-sensitizing or anti-inflammatory effects in patients with NASH have been conducted, one of which is ursodeoxycholic acid (UDCA), a tertiary bile acid. Between 1994 and 2008, four prospective randomized, double-blind, placebo-controlled studies of the treatment of NASH with UDCA were conducted. The first study, by Lindor et al., compared the impact of 13-15 mg/kg/day of UDCA to a placebo. The second study by Dufour et al. had an additional third arm that administered combination therapy with UDCA and vitamin E. The third and fourth studies by Leuschner et al. and by Ratziu et al. evaluated high doses of UDCA at 25-35 mg/kg/day, and used liver biopsies and serum liver enzyme levels to evaluate the impact of UDCA. With the exception of Ratziu et al.'s study, which was lacking a second liver biopsy, none of these studies showed any significant differences in the treatment of NASH with UDCA compared with a placebo. However, Dufour et al. did observe a significant improvement of NASH with the combination (UDCA/VitE) vs placebo therapy, whereas UDCA monotherapy was not effective in the treatment of NASH. Nevertheless, the effects of other bile acids and combination therapies need to be explored.

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Elevated transaminases in asymptomatic patients can be detected in more than 5 % of the investigations. If there are no obvious reasons, the finding should be confirmed within the next 3 months. Frequent causes are non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol, hepatitis B or C, hemochromatosis and drugs or toxins. Rarer causes are autoimmune hepatitis, M. Wilson and α1-antitrypsine deficiency. There are also non-hepatic causes such as celiac disease or hemolysis and myopathies in the case of an exclusive increase of ASAT. I recommend a two-step investigational procedure; the more frequent causes are examined first before the rare causes are studied. The value of the proposed investigations is discussed.

Brain activation during craving for alcohol measured by positron emission tomography

OBJECTIVE: Craving for alcohol is probably involved in acquisition and maintenance of alcohol dependence to a substantial degree. However, the brain substrates and mechanisms that underlie alcohol craving await more detailed elucidation. METHOD: Positron emission tomography was used to map regional cerebral blood flow (CBF) in 21 detoxified patients with alcohol dependence during exposure to alcoholic and non-alcoholic beverages. RESULTS: During the alcohol condition compared with the control condition, significantly increased CBF was found in the ventral putamen. Additionally, activated areas included insula, dorsolateral prefrontal cortex and cerebellum. Cerebral blood flow increase in these regions was related to self-reports of craving assessed in the alcoholic patients. CONCLUSIONS: In this investigation, cue-induced alcohol craving was associated with activation of brain regions particularly involved in brain reward mechanisms, memory and attentional processes. These results are consistent with studies on craving for other addictive substances and may offer strategies for more elaborate studies on the neurobiology of addiction.

Magic angle spinning magnetic resonance: a novel method opening up translational research into NAFLD?

NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) are of increasing importance, both in connection with insulin resistance and with the development of liver cirrhosis. Histological samples are still the 'gold standard' for diagnosis; however, because of the risks of a liver biopsy, non-invasive methods are needed. MAS (magic angle spinning) is a special type of NMR which allows characterization of intact excised tissue without need for additional extraction steps. Because clinical MRI (magnetic resonance imaging) and MRS (magnetic resonance spectroscopy) are based on the same physical principle as NMR, translational research is feasible from excised tissue to non-invasive examinations in humans. In the present issue of Clinical Science, Cobbold and co-workers report a study in three animal strains suffering from different degrees of NAFLD showing that MAS results are able to distinguish controls, fatty infiltration and steatohepatitis in cohorts. In vivo MRS methods in humans are not obtainable at the same spectral resolution; however, know-how from MAS studies may help to identify characteristic changes in crowded regions of the magnetic resonance spectrum.

Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population

Non-alcoholic fatty liver disease (NAFLD) is associated with features of the metabolic syndrome (MetS) and may be an expression of the syndrome within the liver. Using screening data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n = 42 149), we examined whether alanine aminotransferase (ALT), a biomarker for NAFLD, clustered with features of MetS and whether the clusters differed across global geographic regions.

The metabolomic window into hepatobiliary disease

The emergent discipline of metabolomics has attracted considerable research effort in hepatology. Here we review the metabolomic data for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), alcoholic liver disease (ALD), hepatitis B and C, cholecystitis, cholestasis, liver transplantation, and acute hepatotoxicity in animal models. A metabolomic window has permitted a view into the changing biochemistry occurring in the transitional phases between a healthy liver and hepatocellular carcinoma or cholangiocarcinoma. Whether provoked by obesity and diabetes, alcohol use or oncogenic viruses, the liver develops a core metabolomic phenotype (CMP) that involves dysregulation of bile acid and phospholipid homeostasis. The CMP commences at the transition between the healthy liver (Phase 0) and NAFLD/NASH, ALD or viral hepatitis (Phase 1). This CMP is maintained in the presence or absence of cirrhosis (Phase 2) and whether or not either HCC or CCA (Phase 3) develops. Inflammatory signalling in the liver triggers the appearance of the CMP. Many other metabolomic markers distinguish between Phases 0, 1, 2 and 3. A metabolic remodelling in HCC has been described but metabolomic data from all four Phases demonstrate that the Warburg shift from mitochondrial respiration to cytosolic glycolysis foreshadows HCC and may occur as early as Phase 1. The metabolic remodelling also involves an upregulation of fatty acid β-oxidation, also beginning in Phase 1. The storage of triglycerides in fatty liver provides high energy-yielding substrates for Phases 2 and 3 of liver pathology. The metabolomic window into hepatobiliary disease sheds new light on the systems pathology of the liver.

Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.

BACKGROUND & AIMS Unhealthy lifestyles predispose to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePten(flox/flox)), which develop steatohepatitis and HCC spontaneously. METHODS Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 minutes/day, 5 days/week during 32 weeks. RESULTS After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm(3) vs 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR. CONCLUSIONS These data show a benefit of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC.

Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease

With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic NAD(+) levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD(+) biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPR(mt) ), triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1(hep-/-) ), while Apolipoprotein E-deficient (Apoe(-/-) ) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD. CONCLUSION Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD. This article is protected by copyright. All rights reserved.

Physical activity and liver diseases

Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is relatively recent. Most authors focused on non-alcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle cross-talking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting physical activity is considered required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/NASH. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis exercise acutely increases portal pressure, but in longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients exercise is able to improve lean mass, muscle strength and as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be object of future studies given its high potential of providing long-term beneficial effects. Despite evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. This article is protected by copyright. All rights reserved.

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.

Hepatocellular carcinoma and lifestyles.

The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to non-alcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and non-alcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.