Approximately 80 million Americans suffer from fatty liver that has nothing to do with alcoholism. Non-alcoholic fatty liver disease is related to obesity and diabetes, which can lead to more serious liver damage, such as non-alcoholic steatohepatitis (NASH), liver cirrhosis, and liver cancer. Cardiovascular diseases, colorectal cancer and breast cancer are actually the main causes of death in fatty liver patients.
Due to the complexity of the disease, the low efficacy or toxicity of the drug, some drugs in the late stage of development have failed. Although there have been multiple clinical trials in the past few decades, there is currently no FDA-approved NASH drug therapy.
In order to understand the complexity of fatty liver disease progression, a team of scientists from the University of Southern California explored the molecular mechanism of experimental NAFL/NASH. The project led to the discovery of a reasonable therapeutic target gene SH3BP5, also known as SAB.
“This discovery is the culmination of many years of work by the team, including bioinformatics experts, pathologists, students, visiting scholars, and collaborators at the University of Southern California,” said Sanda Win, MD, assistant professor of medical research at GI/Department. Department. Doctor of Medicine from the Keck School of Medicine, University of Southern California.
As Win explained, SAB is a protein in the outer mitochondrial membrane, which is called the energy source of the cell. The biological function of SAB was not known until USC researchers first discovered it 10 years ago. SAB is a key protein. In acetaminophen-induced liver injury models and tumor necrosis factor (TNF)-induced acute liver failure models, the level of SAB determines the severity of liver injury. SAB is a stress-activated kinase (JNK) target that can lead to impaired mitochondrial function and increased toxic reactive oxygen species. Interestingly, SAB gene activation and protein levels increase in diet-induced fatty liver and are associated with disease progression in experimental models and human fatty liver, Win added.
“In these experiments, we can prevent all this progress by deleting the SAB gene in the liver early in these experiments, and then feeding adult animals on a high-fat diet,” said Neil Kaplowitz, professor of medicine and Thomas H. Brem, MD. Head of the Department of Medicine at Keck College.
The project was initiated by a pilot grant funded by the USC Liver Research Center and the Donald E. and Delia Baxter Foundation Faculty Award. The research was recently published in the journal Hepatology of the American Association for the Study of Liver Diseases.
The rats were fed, actually pressurized, high-fat food pellets, with sucrose and fructose water added. Eating high-fat and high-sugar diets for a long time can lead to obesity, diabetes and fatty liver. But even in mice fed a high-fat, high-sugar diet for one year, “if we introduce this antisense drug that targets liver cells, when the mice have established liver inflammation and fibrosis, we will It can reverse everything. To normalize your insulin resistance and significantly reduce the accumulation of fat in the liver and inflammation and fibrosis in the liver,” said Kaplowitz.
One of the benefits, Win said, is that “we don’t need to completely eliminate or eliminate or eliminate SAB protein. The dosage is only to maintain the normal level of SAB and prevent or reverse the progression of the disease.” Utilized by Ionis Pharmaceuticals Inc., Carlsbad, California . The collaborators design and synthesize advanced science of antisense oligonucleotides (ASO), and the team is optimistic about SAB-targeted DNA therapy.
Studies have shown that through moderate behavior changes, liver damage caused by dietary choices can be avoided. Antisense therapy to the mice during the first six months did help them lose weight. The author warns that research involving rats does not always translate into hypotheses about humans.
“There is no doubt that many things that have succeeded in mice will not work in humans,” said Kaplowitz. But “Our data shows that this is a very powerful potential treatment target, and we don’t think there is any disadvantage in directly interfering with SAB by reducing SAB.”