Scientists discover new therapeutic target to treat fatty liver disease
About 80 million Americans suffer from fatty liver disease unrelated to alcohol abuse. Non-alcoholic fatty liver disease is associated with obesity and diabetes, and can lead to more serious liver damage such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. Cardiovascular disease, colorectal cancer, and breast cancer are actually the leading causes of death in patients with fatty liver disease.
Several drugs in late stages of development have failed due to the complexity of the disease, poor efficacy or toxicity of the drugs. Although several clinical trials have been conducted over the past decades, there is currently no FDA approved pharmaceutical treatment for NASH.
To understand the complexity of the progression of fatty liver disease, a team of Founded in 1880, the University of Southern California is one of the world's leading private research universities. It is located in the heart of Los Angeles.
“This discovery is the culmination of years of work by the team including USC bioinformatics specialists, pathologists, students, visiting researchers and collaborators,” said Sanda Win, MD, PhD, Assistant professor of medicine research in the GI / liver division of the department. of Medicine at USC’s Keck School of Medicine.
As Win explains, BSA is a protein in the outer membrane of mitochondria, known as the powerhouse of the cell. The biological function of BSA was not known until researchers at USC discovered it 10 years ago. BSA is a pivotal protein, and the level of BSA determines the severity of liver injury in a model of acetaminophen-induced liver injury and a model of acute tumor necrotic factor (TNF) -induced liver failure. BSA is a target of stress activated kinase (JNK) which then leads to impaired mitochondrial function and an increase in toxic reactive oxygen species. Interestingly, SAB gene activation and protein levels increase in diet-induced fatty liver disease and correlate with disease progression in experimental models and human fatty liver disease, Win added.
“We could prevent all of this progression by removing the BSA gene in the liver at the start of these experiments on adult animals which were then fed a high fat diet,” said Neil Kaplowitz, MD, professor of medicine and Thomas H Brem Chair of Medicine at the Keck School.
The project was started with a pilot grant to Win funded by the USC Research Center for Liver Diseases, and the Donald E. and Delia Baxter Foundation Faculty Fellows Award. The research was recently published in Hepatology, a journal of the American Association for the Study of Liver Disease.
The mice were fed – supercharged, really – a diet of high fat food pellets with added sucrose and fructose water. Long-term eating of a diet high in fat and sugar causes obesity, diabetes, and fatty liver disease. But even in mice that had been on a diet high in fat and sugar for a year, “if we introduced this antisense targeting liver cells, when the mice had already established disease with inflammation and fibrosis in the liver, we could reverse it all, normalize their insulin resistance and dramatically decrease the buildup of fat in the liver as well as inflammation and fibrosis in the liver, âKaplowitz said.
One of the advantages, Win said, is that âwe don’t need to remove or cut down or eliminate BSA protein entirely. Giving the dose just to maintain the normal level of BSA prevents or reverses the progression of the disease. With the benefit of advanced science in antisense oligonucleotides (ASO), designed and synthesized by collaborators at Ionis Pharmaceuticals Inc., of Carlsbad, Calif., The team is optimistic about SAB targeting DNA therapy.
Research shows how much liver damage – due to food choices – could be prevented with modest changes in behavior. Giving the mice antisense therapy for the first six months actually helped them lose weight. The authors caution that studies involving mice don’t always translate into assumptions about humans.
âThere’s no question that a lot of the things that worked in mice don’t work in humans,â Kaplowitz said. But “our data suggest that this is a very strong potential therapeutic target, and we see no harm in directly interfering with BSA as it decreases.”
About the study
This research was funded by NIH Grants R01DK067215 (NK), Veronica Garrie Budnick Chair in Liver Disease (NK), Donald E. Award and Delia Baxter Foundation Faculty Fellows (SW), Pilot Project Award (SW ) by the USC Research Center for Liver Diseases (P30DK048522), and pilot project (SW) funding by the Rodent Metabolic Core of the Saban Research Institute at Children’s Hospital of Los Angeles.