All cells can adapt their metabolic activity with respect to the availability of various sources of energy, such as glucose. This vital ability makes cells more efficient at absorbing and utilizing these substances, in addition to protecting them against the negative effects of overload. However, exposure to chronically-high glucose levels can result in an adaptive response which is damaging to cells and promoting diseases.
The researchers showed that the enzyme retinol saturase (RetSat) plays a role in the adaptive processes found in liver cells. By studying levels of the enzyme in both slim and obese participants, the researchers found that levels increase in line with body weight. They also analyzed the cells' metabolic pathways and their metabolic adaptation to glucose levels after reducing the enzyme's abundance. The negative metabolic effects associated with excess exposure to glucose were significantly less pronounced in cells that had been modified in this way.
RetSat depletion reduced the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP.
Discussing the results of the study the senior authorconcludes: "The inactivation of retinol saturase activity may offer a new approach to the treatment of metabolic liver disease and its associated problems, such as fatty liver disease and dyslipidemia." As a next step, the researchers are planning to identify the mechanisms involved, and to test whether other cell types also need the enzyme to adapt to changing glucose levels.
New regulator of liver metabolism discovered
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