Research Study Establishes Possible Genetic Marker for Steatohepatits
Researchers at Cincinnati Children's have published a study that establishes a connection between the protein augmenter of liver regeneration (ALR) and the pathogenesis of steatohepatitis, a disease linked to obesity that is becoming more prevalent in the pediatric population.
The study, featured in the February 2015 issue of Gastroenterology, used a new mouse model with liver-specific deletion of ALR to demonstrate that ALR is required for mitochondrial function and lipid homeostasis in the liver. The researchers began creating the mouse model in Pittsburgh in 2008 based on their published findings that ALR is a mitochondrial protein and a survival factor for the liver cells, and are the first to use it in lab research.
"The knockout mice we studied developed heavy steatosis within two weeks after birth, that progressed to steatohepatitis, fibrosis and hepatocellular carcinoma by one year," says Chandrashekhar R. Gandhi, PhD, professor in the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's and principal investigator for the study. "A two-week old mouse is equivalent in age to a young human." Dr. Gandhi's laboratory, as described in the paper, has already found eight novel single nucleotide polymorphisms in the human ALR gene. "It is likely that some of these may be associated with predisposition to develop non-alcoholic steatohepatitis. Thus, we suspect that an ALR deficiency could be a genetic marker for steatohepatitis, and that a human with an ALR deficiency or anomaly may be more susceptible to developing steatohepatitis early in life, especially when other risk factors are present."
Previous research has already established a correlation between a high-fat diet and steatohepatitis. The next step, Dr. Gandhi says, is to investigate a possible connection between a high-fat diet, ALR deficiency and the onset of steatohepatitis-related pathologies. His lab is currently building on the ALR research study findings by:
- Testing a hypothesis that a high-fat diet makes mice with low ALR levels more susceptible to steatohepatitis.
- Analyzing serum samples from select pediatric patients in the medical center's steatohepatitis clinic and liver transplant clinics to determine if there may be a genetic link between ALR changes and predisposition to develop nonalcoholic fatty liver disease.
"We hope that these efforts will bring us closer to an understanding of how steatohepatitis develops in children, and how interventions such as a low-fat diet could prevent or delay its onset," says Dr. Gandhi.
Read the study, Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice .
Read more about our Steatohepatitis Center.