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Background and Aim: Chronic inflammation links closely to insulin resistance and lipid metabolism in nonalcoholic fatty liver disease (NAFLD). Macrophage M1 activation plays an important role in the initiation and continuing of pro‐inflammatory response of NAFLD. Our study was to investigate whether macrophage M1/M2 polarization switching would affect hepatic inflammation and lipid metabolism through modulation of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) activity in vivo and in vitro. Methods: RAW264.7 macrophages were treated with different fatty acids, and cell culture supernatants were collected to prepare conditioned media (CM). Different co‐culture systems between primary hepatocytes and CM from macrophages were established. A PPAR‐γ agonist or antagonist was administered to regulate PPAR‐γ activity and macrophage polarization. M1/M2 phenotype markers, inflammatory signaling pathway, and lipid‐related genes expression were determined. Wild‐type C57BL/6 mice were fed a high‐fat diet to induce NAFLD and given rosiglitazone to regulate PPAR‐γ activity in vivo. Results: Saturated fatty acids induced M1‐polarized macrophages while polyunsaturated fatty acids induced M2‐polarized macrophages. M1‐polarized macrophages significantly promoted lipid synthesis and accumulation in primary hepatocytes through upregulation of a toll‐like receptor 4 (TLR4)/NF‐κB signaling pathway. The PPAR‐γ agonist made lipid‐induced M1‐polarized macrophages switch to an M2‐predominant phenotype, while PPAR‐γ antagonist had the opposite effect. Macrophage polarization shifting subsequently affected lipid metabolism in primary hepatocytes. Administration of rosiglitazone improved high‐fat diet induced hepatic steatosis and lipid metabolism through reducing hepatic TLR4/NF‐κB expression and M1‐polarized Kupffer cells. Conclusions: Lipid‐induced macrophage M1 polarization promoted hepatic lipid metabolism. Modulation of PPAR‐γ activity could shift macrophage polarization and subsequently affect lipid metabolism. Upregulation of the TLR4/NF‐κB signaling pathway is closely linked to dysregulated lipid metabolism in NAFLD. [ABSTRACT FROM AUTHOR]

Performance and advances in liver surgery makes remarkable progress of the understanding of liver regeneration. Liver regeneration after liver resection has been widely researched, and the underlying mechanism mostly concerns proliferation of hepatocytes and the influence by inflammation through activation of Kupffer cells and the other parenchymal cells, the second regenerative pathway by hepatic progenitor cells (HPCs), inducing angiogenesis, remodeling of a extracellular matrix (ECM), and termination mechanisms. New clinical surgeries and the updated multiomics analysis are exploiting the remarkable progress, especially in immune regulation and metabolic process of two emerging hallmarks. This review briefly represents a systemic outline of eight hallmarks, including hepatocyte proliferation, contribution of hepatic progenitor cells, inducing angiogenesis, reprogramming of the extracellular matrix, apoptosis and termination of proliferation, inflammation, immune and metabolic regulation, which are set as organizing characteristics of postoperative liver regeneration and future directions of refining treatment targets. [ABSTRACT FROM AUTHOR]

A review of the article "Differences in Innate Immune Signaling Between Alcoholic and Non-Alcoholic Steatohepatitis" by Jan Petrasek, Timea Csak, and Michal Ganz, which appeared in the "Journal of Gastroenterology and Hepatology" on October 12, 2012, is presented.

A review of the article " Interaction of Hepatic Stellate Cells With Diverse Types of Immune Cells: Foe or Friend?" by Hyon-Seung Yi and Won-ll Jeong, which appeared in the "Journal of Gastroenterology and Hepatology" on November 10, 2013, is presented.

Activation of hepatic stellate cells (HSC) to a myofibroblast-like phenotype is the pivotal event in liver fibrosis. In uninjured liver, HSC are quiescent and non-dividing, but upon liver injury these cells undergo a dramatic change in phenotype which generates activated myofibroblast-like HSC. The change in phenotype is underpinned by a global change in gene expression with hundreds of genes being up- or downregulated. Molecular events that orchestrate changes in gene expression take place at the level of chromatin packaging which is altered through three main processes: histone modifications, DNA methylation, and silencing by non-coding RNAs. The present review focuses on the epigenetic regulation of HSC activation. [ABSTRACT FROM AUTHOR]

Background and Aim: The mechanism of pancreatic fibrosis is unclear. Taurine is used in the clinical treatment of a wide variety of diseases, but its effect on improving pancreatic fibrosis is unknown. We examined whether a diet with added taurine improves pancreatic fibrosis induced by dibutyltin dichloride (DBTC) in an experimental chronic pancreatitis rat model. In addition, we examined the influence of taurine on pancreatic stellate cells. Methods: Pancreatic fibrosis was induced by DBTC. Rats were fed a taurine-containing diet or a normal diet and were killed at 4 weeks. Pancreatic stellate cells were isolated from male Wistar rats. Cultured pancreatic stellate cells were incubated with or without taurine chloramine. Type I collagen and transforming growth factor-β1 secretion was evaluated by ELISA, and matrix metalloproteinase activity was assessed by gelatin zymography. Interleukin-6, interleukin-2, and transforming growth factor-β1 levels in the supernatants of pancreatic tissue homogenates were measured. Results: Pancreatic fibrosis induced by DBTC was improved remarkably by the oral administration of the taurine-containing diet. Taurine chloramine decreased type I collagen, transforming growth factor-β1, and matrix metalloproteinases 2 of the pancreatic stellate cell culture supernatant. Increased interleukin-6 and decreased interleukin-2 were found in the supernatants of the pancreatic tissue homogenates of DBTC-induced pancreatitis rats compared with other groups. Conclusion: The oral administration of taurine improves pancreatic fibrosis. Taurine chloramine inhibits transforming growth factor-β1 produced from activated pancreatic stellate cells and improves pancreatic fibrosis. [ABSTRACT FROM AUTHOR]

Alcohol-associated acute and chronic pancreatitis occur in a minority of alcohol users, suggesting that most drinkers are protected from pancreatic diseases while a subset is susceptible. Ongoing studies suggest that the pathophysiology is complex and can involve multiple genetic and environmental pathways and stochastic events. Both rat models and human genetic epidemiology studies have been used to understand susceptibility and modifying factors in humans. Rat studies suggest that different types of altered pancreatic physiology occur depending on dose, they occur rapidly and that alcohol changes the immune response to recurrent pancreatic injury. Human studies suggest that PRSS1 and SPINK1 mutation increase the pancreas’ susceptibility to alcohol-associated pancreatitis, and that tobacco smoking, and some factors, affect disease progression. [ABSTRACT FROM AUTHOR]

Editorial. Investigates whether oxidative stress initiates hepatic stellate cell activation. Causes of oxidative stress; Substances with antioxidant properties that have antifibrotic effects.

Abstract Reactive oxygen species (ROS) are important cytotoxic and signalling mediators in the pathophysiology of inflammatory liver diseases. They can be generated by resident and infiltrating phagocytes and/or intracellularly in every liver cell type after stimulation with cytokines. Although ROS are able to cause cell destruction by massive lipid peroxidation, in most cases, ROS are more likely to modulate signal transduction pathways by affecting redox-sensitive enzymes, organelles (e.g. mitochondria) and transcription factors. Thus, ROS can directly induce and/or regulate apoptotic and necrotic cell death. In addition, ROS can have indirect effects on the pathophysiology by supporting protease activity through inactivation of antiproteases and by modulating the formation of inflammatory mediators and adhesion molecules. Many of the effects of ROS may occur simultaneously or sequentially in the pathophysiology. Although mainly described in this review as detrimental, ROS are essential for host-defence functions of phagocytes and can modulate the formation of mediators involved in regulating sinusoidal blood flow and liver regeneration. Thus, continuous efforts are necessary to improve our understanding of the role of ROS in the pathophysiology of inflammatory liver diseases and to discover therapeutic interventions that selectively target the negative effects of reactive oxygen formation. [ABSTRACT FROM AUTHOR]

AbstractChemokines are implicated in the pathogenesis of alcoholic liver disease in humans and in experimental models of alcohol intoxication. The major sources of these chemokines are Kupffer cells which represent more than 80% of tissue macrophages in the body. Kupffer cells are highly responsive to the effects of ethanol, endotoxin and human immunodeficiency virus (HIV)-1 glycoprotein120. These agents, either independently or in combination, may exacerbate the production of chemokines. Chemokines are agents that are highly chemotactic to mononuclear cells and granulocytes. The levels of these chemokines in sera and tissue are elevated in patients with alcoholic hepatitis, alcoholic cirrhosis, diseased livers, viral hepatitis, and in experimental models of chronic alcohol intoxication. Alcohol-induced influx of endotoxin from the gut into the portal circulation is suggested to play an important role in the activation of Kupffer cells which leads to enhanced chemokine release. The up-regulation of chemokines during alcohol consumption is selective. During the early phase of alcoholic liver disease, C-X-C or α- chemokines predominate. This is also associated with neutrophilic infiltration of the liver. In the later stage, up-regulation of C-C or β-chemokine production and migration of mononuclear cells into the liver are observed, and this may lead to liver cirrhosis. Selective up-regulation of chemokine synthesis and release may involve differential modulation of the transcription factors required for chemokine gene expression. Increased cytokine release following alcohol consumption may also regulate chemokine secretion in Kupffer cells via paracrine and autocrine mechanisms and vice versa. In addition, infection with HIV-1 may further compromise the liver to more damage. During HIV-1 infection, a pre-existing liver disease superimposed on chronic alcohol consumption may also exacerbate HIV-1 replication and lymphocytic infiltration in the liver, because of the ability of HIV-1 gp120 to stimulate chemokine production by Kupffer cells and stimulate migration of inflammatory leucocytes in the liver. [ABSTRACT FROM AUTHOR]

Abstract The participation of matrix metalloproteinases (MMP) and their specific inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMP), in both the formation and degradative recovery processes of liver fibrosis were mainly reviewed from the molecular biological aspect. Since authors first reported increased activity of interstitial collagenase in the early stage of hepatic fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have also demonstrated increased activity biologically and histochemically. However, species-specific differences in response have been found and gene-level research on the rat model has not demonstrated increased mRNA transcription of collagenase. It has also been clarified that activated stellate cells can also produce matrix components. Very recently, authors observed the participation of interstitial collagenase in the recovery from experimental hepatic fibrosis by using polymerase chain reaction northern blotting and in situ hybridization. The in situ hybridization findings not only demonstrated the cells responsible for interstitial collagenase, but also suggested a great deal about the mechanism of recovery from fibrosis. Hepatic stellate cells are activated via the expression of c-myb and nuclear factor-κB (NFκB) which is induced by oxidative stress, and inhibited by antioxidant (1-α-tocopherol) and butylated hydroxytoluene. The activation mechanism is now being revealed. The relationship between the activation mechanism of stellate cells and the production and secretion of MMP and TIMP in the formation and recovery process of hepatic fibrosis should be investigated from the promoter gene level. This approach might help develop a new strategy for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Ursodeoxycholic acid is used in the treatment of acute and chronic intrahepatic cholestasis because it ameliorates cholestasis and protects hepatocytes. However, few studies have examined the effect of bile acids on the function of Kupffer cells. Methods: The effect of various bile acids on cultured rat Kupffer cells was studied in terms of phagocytic activity in response to latex particles and morphological alterations. Video-enhanced differential interference contrast microscopy was used. Results: Taurochenodeoxycholic acid and taurodeoxycholic acid reduced the number of latex particles incorporated into Kupffer cells, but taurocholic and tauroursodeoxycholic acids enhanced phagocytosis of latex particles. Inhibition of phagocytosis by taurochenodeoxycholic acid or taurodeoxycholic acid was essentially dose dependent. Tauroursodeoxycholic acid also enhanced phagocytosis by Kupffer cells in which phagocytosis had been reduced by pretreatment with taurochenodeoxycholic acid or taurodeoxycholic acid. Incorporated latex particles had a distinct translocation speed of 0.084 ± 0.024 μm/s (mean maximum speed ± SD); the speed was in the same range with tauroursodeoxycholic acid treatment. Tauroursodeoxycholic acid induced a 56% expansion of cytoplasm, associated with increased ruffling and movement of intracellular organelles. Conclusions: These observations suggest that tauroursodeoxycholic acid enhances membrane trafficking without changing translocation speed. [ABSTRACT FROM AUTHOR]