The University of Texas Health Science Center at San Antonio
08/20/2024 | News release | Distributed by Public on 08/20/2024 10:34
Study: Dysregulation in bioenergetic process linked to rapid onset of non-alcoholic fatty liver disease
Every molecule in cellular metabolism has a role to play. A breakdown in any part of this delicate balance can cause a chain reaction of negative health conditions.
Acetyl-CoA is a necessary molecule in the bioenergetic process because it converts fuel sources into energy for the cells. For mammals, this fuel is usually glucose, which is converted to pyruvate or lactate. When glucose is scarce, the body can pivot and use acetyl-CoA synthetase short-chain family member 1 (ACSS1) to connect acetate and CoA to create acetyl-CoA. ACSS1, acetate and acetylation are all central to regulation of many cellular metabolism processes in both fed and fasting states.
In a study published May 17 in Science Advances, scientists from The University of Texas Health Science Center at San Antonio show in a mouse model how dysregulation of ACSS1 acetylation can lead to changes in metabolism, cellular senescence and non-alcoholic fatty liver disease.
The primary investigator for the study is David Gius, MD, PhD, professor in the Department of Radiation Oncology, assistant dean of research and associate director for translational research at the Mays Cancer Center at UT Health San Antonio.
Gius said work on this model began in 2008. The study highlights the damaging effects of dysregulation in the cellular metabolic network, which made the mice unable to adapt to fasting. In just two days, scientists viewed significant changes to the morphology and histology of the liver.
When there is little or no food, humans survive by utilizing fatty acids stored in the body, which are turned into energy for the cells to use. Gius said humans are well-adapted to go long periods of time without eating by using stored fat. During periods of nutrient deprivation, ACSS1 facilitates the conjoining of acetate and CoA to create acetyl-CoA. Acetate aids in the generation of adenosine 5'-triphosphate (ATP), which is used for energy and lipogenesis in the liver in the absence of usual nutritional sources.
To illustrate the metabolic role of ACSS1 acetylation in vivo, a knock-in mouse model was produced in which lysine at amino acid position 635 was mutated to glutamine. A knock-in model is created by adding a mutated gene at a targeted point in the mouse's DNA. Gius said this alteration mimics acetylated lysine due to the similarity of structure and neutral charge. In the fed state, male mouse models were smaller and had higher metabolic rates and blood acetate levels. Mice that were fasted for 48 hours additionally had hypothermia, reduced ATP and lactate levels and liver irregularities consistent with non-alcoholic fatty liver disease. The disruption in ACSS1 acetylation, exacerbated in a fasting state, caused a breakdown of the cellular metabolic process, leading to adverse health conditions including symptoms of non-alcoholic fatty liver disease.
"What we have shown is that when you alter the acetylation of this protein and then you fast them (the mouse models), you get acute onset non-alcoholic fatty liver disease," Gius said.
Non-alcoholic fatty liver disease occurs when too much fat accumulates in the liver. This silent killer usually does not have any symptoms. According to the American Liver Foundation, it is estimated that 25% of adults in the United States, and about 38% of adults in Texas have non-alcoholic fatty liver disease. The disease is more prevalent in Hispanic populations, people with obesity and type 2 diabetics. If liver damage continues, non-alcoholic fatty liver disease can lead to cirrhosis and hepatocellular carcinoma, or liver cancer. There are currently no medications available to treat non-alcoholic fatty liver disease. If liver damage is halted in the early stages, diet and lifestyle changes slow progression of the disease and can reverse the damage in some cases.
"We have a model where you can induce fatty liver (disease) in two days - 48 hours - which means you can investigate the mechanisms and therapeutic interventions in a much easier way," Gius said.
Gius hopes to build off this study to create an improved model for future study of non-alcoholic fatty liver disease and liver cancer.
This study is part of the institutional commitment of UT Health San Antonio and the Mays Cancer Center to investigate the processes and potential treatments for liver cancer, an endemic health concern in the central and south Texas regions.
Xu, Guogang; Quan, Songhua; Schell, Joseph; Gao, Yucheng; Varmazyad, Mahboubeh; Sreenivas, Prethish; Cruz, Diego; Jiang, Haiyan; Pan, Meixia; Han, Zianlin; Palavicini, Juan Pablo; Zhao, Peng; Sun, Xiaoli; Marchant, Erik D.; Rasmussen, Blake B.; Li, Guannan; Katsumura, Sakie; Morita, Masahiro; Munkacsy, Erin; Horikoshi, Nobuo; Chocron, E. Sandra; Gius, David. Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered metabolism, cell senescence, and nonalcoholic fatty liver disease. Published May 17, Sci. Adv.10,eadj5942(2024).DOI:10.1126/sciadv.adj5942
Read more about Dr. Gius and his research:
A long-term ketogenic diet accumulates aged cells in normal tissues
Drs. Gius, Patterson accepted into prestigious Association of American Physicians