Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the most frequent chronic liver disorders, and their advanced forms - alcoholic steatohepatitis and nonalcoholic steatohepatitis - are the most frequent conditions leading to liver cirrhosis and hepatocellular carcinoma worldwide. NAFLD is considered as the hepatic manifestation of the metabolic syndrome. With the pandemic rise of obesity, the incidence of NAFLD is also further increasing, and considering the life style in modern societies, there is a significant overlap of (risk factors causing) NAFLD and (alcohol consumption predisposing for) ALD at least in Western countries. Epidemiological studies propose a causative link between chronic alcohol consumption and progressive liver disease in obese individuals. Furthermore, experimental studies indicate combined pathological effects of alcohol and obesity or fatty acid levels, respectively, on hepatocellular lipid accumulation and injury as well as hepatic inflammation, fibrosis and cancerogenesis. Notably, these combined pathological effects are in part additive but partly even synergistic. And importantly, alcohol does already exhibit synergistic pathological effects with obesity at moderate doses. This indicates significant differences in the dose threshold for hepatotoxic alcohol effects in lean and obese subjects and herewith also has important implications for recommendations for ‘safe' alcohol consumption. The purpose of this brief review is to update the knowledge on the combined effects of alcohol and obesity on the development and progression of liver disease. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important interactive effects of either condition with regard to crucial triggers of liver injury.

Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice

Objective Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown. Design Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients. Results Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers. Conclusions Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization of xanthohumol could enhance the bioavailability and biological efficacy of xanthohumol in a Western-type diet (WTD) induced model of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). After 3 weeks feeding with WTD, XN was additionally applied per oral gavage as micellar solubilizate (s-XN) or native extract (n-XN) at a daily dose of 2.5 mg/kg body weight for a further 8 weeks. Control mice received vehicle only in addition to the WTD. WTD-induced body weight-gain and glucose intolerance were significantly inhibited by s-XN application. Furthermore, WTD-induced hepatic steatosis, pro-inflammatory gene expression (MCP-1 and CXCL1) and immune cell infiltration as well as activation of hepatic stellate cells (HSC) and expression of collagen alpha I were significantly reduced in the livers of s-XN-treated mice compared to WTD controls. In contrast, application of n-XN had no or only slight effects on the WTD-induced pathological effects. In line with this, plasma XN concentration ranged between 100–330 nmol/L in the s-XN group while XN was not detectable in the serum samples of n-XN-treated mice. In conclusion, micellar solubilization enhanced the bioavailability and beneficial effects of xanthohumol on different components of the metabolic syndrome including all pathological steps of NAFLD. Notably, this was achieved in a dose more than 10-fold lower than effective beneficial doses of native xanthohumol reported in previous in vivo studies.

Xanthohumol is the principal prenylated flavonoid of the female inflorescences of the hop plant. In recent years, various beneficial xanthohumol effects including anti-inflammatory, antioxidant, hypoglycemic activities, and anticancer effects have been revealed. This review summarizes present studies indicating that xanthohumol also inhibits several critical pathophysiological steps during the development and course of chronic liver disease, including the activation and pro-fibrogenic genotype of hepatic stellate cells. Also the various mechanism of action and molecular targets of the beneficial xanthohumol effects will be described. Furthermore, the potential use of xanthohumol or a xanthohumol-enriched hop extract as therapeutic agent to combat the progression of chronic liver disease will be discussed. It is notable that in addition to its hepatoprotective effects, xanthohumol also holds promise as a therapeutic agent for treating obesity, dysregulation of glucose metabolism and other components of the metabolic syndrome including hepatic steatosis. Thus, therapeutic xanthohumol application appears as a promising strategy, particularly in obese patients, to inhibit the development as well as the progression of non-alcoholic fatty liver disease.

Background: Silymarin derived from the milk thistle plant “Silybum marianum” is composed of four major flavonolignans. Clinical as well as experimental studies indicate hepatoprotective effects of silymarin. However, the underlying mechanisms are only incompletely understood. The aim of this study was to assess the effect of oral administration of a defined silymarin extract in the model of acute carbon tetrachloride (CCl₄) induced liver injury. Methods: A single dose of a silymarin extract (SE; 20 or 100 mg/kg body weight) was given to rats by oral gavage. Subsequently, rats were injected with a single dose of CCl₄ (2 ml/kg body weight). Results: After 24h, analysis of liver to body weight ratio, serum levels of transaminases and histological analysis revealed a marked liver damage which was inhibited by SE in a dose dependent manner. CCl₄-induced expressions of pro-inflammatory and pro-fibrogenic genes were significantly reduced in SE treated rats. Molecular analysis revealed that SE reduced the expression of the pro-inflammatory chemokine MCP-1, the pro-fibrogenic cytokine TGF-beta as well as collagen I in isolated human hepatic stellate cells (HSC), which are the key effector cells of hepatic fibrosis. Conclusion: Oral administration of the tested silymarin extract inhibited hepatocellular damage in a model of acute liver injury. Moreover, we newly found that the silymarin extract had direct effects on pro-inflammatory and pro-fibrogenic gene expression in HSCs in vitro. This indicates that direct effects on HSC also contribute to the in vivo hepatoprotective effects of silymarin, and further promote its potential as anti-fibrogenic agent also in chronic liver disease.