Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner.

Findings about chronic complex diseases are difficult to extrapolate from animal models to humans. We reason that organs may have core network modules that are preserved between species and are predictably altered when homeostasis is disrupted. To test this idea, we perturbed hepatic homeostasis in mice by dietary challenge and compared the liver transcriptome with that in human fatty liver disease and liver cancer.

Macrophage Coordination of the Interferon Lambda Immune Response.

Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ.

The role of AdipoR1 and AdipoR2 in liver fibrosis.

Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl) model of liver fibrosis.

Adiponectin confers protection from acute colitis and restricts a B cell immune response.

Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer. Recent data also suggest a protective role in colitis. However, the precise molecular mechanisms by which adiponectin and its receptors modulate colitis and the nature of the adaptive immune response in murine models are yet to be elucidated.

Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells.

Unlabelled: Adiponectin protects against liver fibrosis, but the mechanisms have not been fully elucidated. Here, we showed that adiponectin upregulated inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) and protein expression in hepatic non-parenchymal cells, particularly in hepatic stellate cells (HSCs), and increased nitric oxide (NO2-/NO3-) concentration in HSC-conditioned medium. Adiponectin attenuated HSC proliferation and migration but promoted apoptosis in a NO-dependent manner.

Effect of resveratrol on experimental non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are increasing clinical problems for which effective treatments are required. The polyphenol resveratrol prevents the development of fatty liver disease in a number of experimental studies. We hypothesized that it could revert steatohepatitis, including hepatic inflammation and fibrosis, in an experimental NASH model.

Adiponectin reduces hepatic stellate cell migration by promoting tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion.

Hepatic stellate cells (HSC) are central players in liver fibrosis that when activated, proliferate, migrate to sites of liver injury, and secrete extracellular matrix. Obesity, a known risk factor for liver fibrosis is associated with reduced levels of adiponectin, a protein that inhibits liver fibrosis in vivo and limits HSC proliferation and migration in vitro. Adiponectin-mediated activation of adenosine monophosphate-activated kinase (AMPK) inhibits HSC proliferation, but the mechanism by which it limits HSC migration to sites of injury is unknown.

Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host-targeting agents.

Direct-acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed. Lipid metabolism is closely linked with hepatitis C virus (HCV) replication, and endocannabinoids are major regulators of lipid homeostasis. The cannabinoid 1 (CB1) receptor mediates these effects in the liver.

Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause?

Unlabelled: Advanced liver fibrosis in nonalcoholic steatohepatitis (NASH) is often accompanied by a reduction in hepatic fat to the point of complete fat loss (burnt-out NASH), but the mechanisms behind this phenomenon have not been elucidated. Adiponectin is raised in cirrhosis of any cause and has potent antisteatotic activity. In this study we examined 65 patients with advanced biopsy-proven NASH (fibrosis stage 3-4) and 54 with mild disease (fibrosis stage 0-1) to determine if disappearance of steatosis correlated with changes in serum adiponectin.

Leptin and acetaldehyde synergistically promotes αSMA expression in hepatic stellate cells by an interleukin 6-dependent mechanism.

Background: The mechanisms whereby patients with obesity/overweight are more susceptible to alcohol-associated liver fibrosis are unclear. Leptin, a peptide hormone secreted by white adipose tissue is increased in association with overweight/obesity and is recognized as mediator of liver fibrosis. We sought to assess whether leptin contributes to alcoholic liver fibrosis by in vitro studies in hepatic stellate cells (HSC).

Kupffer cells mediate leptin-induced liver fibrosis.

Background & Aims: Leptin has profibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).

Methods: HSCs from Sprague-Dawley rats were exposed to leptin and expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF/CCN2) was assessed.