Fatty liver disease is a "disease of wealth" caused by overnutrition in the eyes of most people. In fact, there are also many emaciated fatty liver disease patients, accounting for 20% of the total number of fatty liver disease patients. As early as 1929, pediatrician Cicelli Williams discovered that many babies in Ghana's coastal areas suffer from malnutrition due to early weaning, and although these sick children are skinny, they often suffer from severe fatty liver disease. In addition to malnutrition in sick children, people with anorexia nervosa also suffer from fatty liver disease. What is even more surprising is that in people who rely on fasting to achieve rapid weight loss, the incidence of fatty liver disease will also be significantly higher than that of healthy people.
Why do obese people with overnutrition and emaciated people who are malnourished develop fatty liver disease?
"When we feel lost, fruit flies can always guide us in the direction of the way." As Michael Young, winner of the 2017 Nobel Prize in Physiology or Medicine, put it, "It's fruit flies that put us on the right path again and again." Even as the giant wheels of evolution roll forward, we can still catch the shadow of mammals and even humans from fruit flies. "The whole genome sequencing results show that the degree of homology between Drosophila melably and the human genome is as high as 60%, covering 77% of the pathogenic genes of human genetic diseases, which is an ideal disease model." Drosophila larvae are highly similar to human liver cells, and will accumulate a large number of lipid droplets under the stimulation of hunger, simulating human fatty liver disease and providing an ideal entry point for understanding the clinical manifestations of fatty liver disease caused by malnutrition. It is based on the above homologous properties and the strong advantages of Drosophila genetics that the pigmented cells provide an ideal research system for the study of the molecular mechanism of malnutrition causing fatty liver disease.
The research group of Zhu Jian, a researcher at the School of Life Sciences of Peking University and the Peking University-Tsinghua Joint Center for Life Sciences, recently published a research paper entitled "Essential Amino Acids in the Diet Induce Ubiquitination Modification to Improve Fatty Liver Disease" in Molecular Cells online. The research team used fruit fly larvae pigment cells as a research system and found that insufficient intake of essential amino acids is the "culprit" that causes malnourished people to suffer from fatty liver disease. When essential amino acids are scarce, the E3 ubiquitin ligase Ubr1 in hepatocytes is inactivated and cannot catalyze the polyubiquitination degradation of the lipid drop protection protein Plin2. Elevated levels of the Plin2 protein inhibit the breakdown of liver fat, resulting in fatty liver disease.
According to Zhu Jian's research group, Ubr1 is an important essential amino acid receptor in hepatocytes, but unlike known amino acid-binding proteins, it can distinguish between essential amino acids and non-essential amino acids. The 7 essential amino acids (arginine, lysine, histidine, leucine, isoleucine, tryptophan and phenylalanine) bind directly to and activate Ubr1, prompting it to catalyze the ubiquitination degradation of substrate Plin2, thereby alleviating fat accumulation in liver cells. As two branched-chain amino acids, leucine and isoleucine have the strongest ability to activate Ubr1. The addition of leucine or isoleucine to food can significantly improve the resistance of Drosophila larvae to fat accumulation in dyschromatocytes under starvation conditions. Therefore, for malnourished people, appropriate supplementation of essential amino acids, especially branched-chain amino acids, has important guiding significance for the prevention of fatty liver disease.
As the world's highest incidence of chronic liver disease, fatty liver disease seriously threatens human life and health. Despite the huge amount of manpower, material and financial resources, no drug for fatty liver disease has been approved for marketing. So, is it possible to achieve treatment of fatty liver disease by activating Ubr1?
Zhu Jian's group found that the activation of Ubr1 by essential amino acids depends on the release of its self-inhibiting effect. By de-suppressing Ubr1, they constructed a continuously activated form of Ubr1 mutant. In the absence of amino acid binding, the continuously activated form of Ubr1 mutant can also efficiently catalyze the ubiquitination degradation of Plin2, significantly improving fatty liver disease caused by insufficient amino acid intake. It is worth mentioning that through improvements in the technique of isolating contained peptides, they achieved recombinant expression of the continuously activated form of Ubr1 mutant protein in mouse livers. Over a 2-week period, the expression of the continuously activated form Ubr1 mutant was able to significantly improve fatty liver disease caused by obesity or high-fat diet, prompting a reduction in liver fat content in mice by more than 40%. Therefore, activating Ubr1 can be used as a potential therapeutic strategy for fatty liver disease, and the fat-soluble small molecules that can specifically bind and activate Ubr1 are expected to become a specific drug for the treatment of fatty liver disease.
(Guangming Daily all-media reporter Jin Haotian)
Source: Guangming Daily all-media reporter Jin Haotian
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