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Appetite-regulating Hormone Ghrelin May Inhibit Inflammation and Liver Fibrosis

Ghrelin, an appetite-regulating hormone produced primarily in the stomach, reduced liver fibrosis, inflammation, and oxidative stress in rats and protected them from both chronic and acute liver injury, according to a study published in the March 2010 issue of Hepatology. Researchers also found that ghrelin levels were lower in chronic hepatitis patients with advanced fibrosis. If confirmed in future studies, ghrelin may have potential as an anti-fibrotic therapy.

Montserrat  Moreno and colleagues from Spain performed a series of laboratory, animal, and human studies to assess whether ghrelin might reduce liver fibrogenesis, or development of fibrosis, related to hepatitis.

There are no approved anti-fibrotic therapies for patients with liver diseases such as hepatitis B or C, the investigators noted as background. Ghrelin is a hormone produced mainly in the stomach and pancreas that triggers hunger. It is also produced by the hypothalamus in the brain and stimulates the pituitary gland to release growth hormone; it appears to have other effects in the body including sleep regulation.

The researchers administered recombinant (manufactured) ghrelin to rats with acute liver injury (caused by carbon tetrachloride toxicity) and chronic or long-term liver injury (caused by bile duct ligation), analyzing disease progression and liver gene expression. They also evaluated response to chronic liver injury in wild-type (normal non-mutated) mice and mice genetically engineered to be ghrelin-deficient.

In addition, the investigators studied the effects of ghrelin in vitro in cultures of primary human hepatic stellate cells, which produce extracellular matrix material such as collagen that builds up to cause fibrosis and cirrhosis (accumulation of scar tissue).

Finally, ghrelin liver gene expression and serum levels were assessed in more than 100 blood samples from patients with chronic liver diseases (including chronic hepatitis C and alcoholic hepatitis) and healthy control subjects. Ghrelin gene polymorphisms (natural variations) were analyzed in patients with chronic hepatitis C.

Results

• In rats with chronic liver damage, recombinant ghrelin treatment decreased the fibrogenic (fibrosis-causing) properties of hepatic stellate cells and accumulation of myofibroblasts (another type of cell that plays a role in fibrosis), reduced altered gene expression, and lessened liver injury.
• Ghrelin also protected rats against acute liver injury and reduced oxidative stress and inflammation.
• Ghrelin-deficient mice with chronic liver injury developed worse liver damage and fibrosis than normal mice.
• Among human patients with chronic liver disease, those with advanced fibrosis had decreased blood levels of ghrelin.
• Ghrelin gene expression in the liver correlated with expression of fibrogenic genes in humans.
• In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (-994CT and -604GA) influenced liver fibrosis progression.

Based on these findings, the study authors concluded, "Ghrelin exerts anti-fibrotic effects in the liver and may represent a novel anti-fibrotic therapy."

Further research is needed to determine whether ghrelin might be a safe and effective treatment for liver fibrosis. Prior studies looking at ghrelin as a therapy for other conditions including anorexia (lack of appetite), cachexia (wasting), and chronic heart failure have shown that it is generally well tolerated.

Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Genotyping and Genetic Diagnosis Unit, Research Foundation, Hospital Clínico Universitario de Valencia, Valencia, Spain; Experimental Hepatic Ischemia-Reperfusion Unit, Centro Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques de Barcelona, Barcelona, Catalonia, Spain; Genomics Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Endocrinology Unit, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.

3/23/10

Reference

M Moreno, JF Chaves, P Sancho-Bru, and others. Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans. Hepatology 51(3): 974-985. March 2010.