Complement Factor D protects mice from ethanol-induced inflammation and liver injury.

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown.

Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice.

Background: Ethanol feeding in mice activates complement via C1q binding to apoptotic cells in the liver; complement contributes to ethanol-induced inflammation and injury. Despite the critical role of C1q in ethanol-induced injury, the mechanism by which ethanol activates C1q remains poorly understood. Secretory IgM (sIgM), traditionally considered to act as an anti-microbial, also has critical housekeeping functions, facilitating clearance of apoptotic cells, at least in part through activation of C1q.

Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1α.

The hypoxia-sensing transcriptional factor HIF1α is implicated in a variety of hepato-pathological conditions; however, the contribution of hepatocyte-derived HIF1α during progression of alcoholic liver injury is still controversial. HIF1α induces a variety of genes including those involved in apoptosis via p53 activation. Increased hepatocyte apoptosis is critical for progression of liver inflammation, stellate cell activation and fibrosis.

The impact of obesity and metabolic syndrome on alcoholic liver disease.

Alcoholic liver disease (ALD) remains a major cause of chronic liver diseases and liver failure. Population-based prospective studies and patient cohort studies have demonstrated that obesity and the metabolic syndrome exacerbate progression of ALD and increase hepatocellular carcinoma (HCC) incidence and mortality. Emerging evidence also suggests a synergism between alcohol and obesity in mortality and HCC incidence.

Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis.

Unlabelled: The effect of moderate alcohol consumption on liver fibrosis is not well understood, but evidence suggests that adenosine may play a role in mediating the effects of moderate ethanol on tissue injury. Ethanol increases the concentration of adenosine in the liver. Adenosine 2A receptor (A2AR) activation is known to enhance hepatic stellate cell (HSC) activation and A2AR deficient mice are protected from fibrosis in mice.

Acute liver injury associated with glucosamine dietary supplement.

A 55-year-old woman taking  over-the-counter (OTC) glucosamine developed symptomatic hepatotoxicity. Several of her liver enzymes were elevated to 10 times the upper limit of normal. One week after discontinuing glucosamine, serum transaminases fell dramatically, with some returning to normal limits.

Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

Background: Correlative evidence indicates that apoptosis is associated with the progression of alcoholic liver disease. If apoptosis contributes to ethanol (EtOH)-induced steatohepatitis and/or fibrosis, then mice deficient in Bid, a key pro-apoptotic Bcl-2 family member, or mice treated with a pan-caspase inhibitor (VX166) should be resistant to EtOH-induced liver injury.

Methods: This hypothesis was tested in mice using a model of chronic, heavy EtOH-induced liver injury, as well as in a model in which moderate EtOH feeding accelerated the appearance of early markers of hepatic fibrosis in response to acute carbon tetrachloride (CCl(4) ) exposure.

Obesity, diabetes mellitus, and liver fibrosis.

Obesity is a global epidemic with more than 1 billion overweight adults and at least 300 million obese patients worldwide. Diabetes is characterized by a defect in insulin secretion or a decrease in sensitivity to insulin, which results in elevated fasting blood glucose. Both obesity and elevated fasting glucose are risk factors for nonalcoholic fatty liver disease, a disease spectrum that includes hepatic steatosis (nonalcoholic fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis.

Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice.

Objective: To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD).

Design/intervention: Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months.

Main Outcome Measures: Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis.