GW study examines impact of nervous system on non-alcoholic fatty liver disease

A team led by Colin Young, PhD, will evaluate the role of brain endoplasmic reticulum stress in the development of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the accumulation of fat in the liver of people who drink little or no alcohol, affects 1 in 3 Americans. NAFLD is a significant risk factor for Type 2 diabetes, insulin resistance, and hepatic carcinoma, and incidence of the disease is increasing with the growing obesity epidemic in the United States.

Colin Young, PhD

Based on previous studies, researchers believe that endoplasmic reticulum (ER) stress, a protein folding process in the brain, is involved in the generation and maintenance of NAFLD. However, changes in the nervous system are not well understood.

Researchers from the George Washington University (GW) have been investigating the role of brain ER stress in NAFLD for three years. Their current study, which received more than $2.4 million from the National Institutes of Health, aims to better understand the role of forebrain and hypothalamic ER stress in obesity induced hepatic sympathetic overactivity and NAFLD development.

"There's mounting evidence that suggests ER stress-induced transcription factor activation is involved in the development of NAFLD," said Colin Young, PhD, assistant professor of pharmacology and physiology at the GW School of Medicine and Health Sciences. "We don't yet understand the changes that occur in the nervous system, however, they are crucial in the acute and long-term regulation of liver metabolism."

Young and his team will examine the role of ER stress in the activation of activator protein-1 (AP-1), a transcription factor that regulates gene expression in response to a variety of stimuli, in hypothalamic neurons during the development of NAFLD.

"To facilitate long-lasting alterations in central nervous system function, there needs to be changes in gene expression through regulation of inducible transcription factors," Young explained. "Dissecting the links between ER stress and transcription factor activation in NAFLD development has the potential to identify new therapeutic targets for the treatment and prevention of this condition."

Researchers will use a combination of innovative imaging, molecular, neuroanatomical and integrative physiological approaches to address the hypothesis that hepatic sympathetic overactivity due to ER stress-induced AP-1 activation in forebrain-hypothalamic circuits is critical in driving NAFLD.