HK2 protein identified as potential treatment target for MASH: Study
Along with S100A11, it contributes to abnormal buildup of fat in the liver
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Two proteins called S100A11 and HK2 contribute to the abnormal buildup of fat in the liver that characterizes steatotic liver disease (SLD), according to a study mainly conducted in mice.
S100A11 suppression was found to alleviate metabolic dysfunction-associated steatohepatitis (MASH), a severe form of SLD, in a mouse model, and these beneficial effects were associated with a reduction in HK2 levels. Also, boosting HK2 production was enough to drive liver fat accumulation both in mice lacking S100A11 and in healthy mice.
The findings point to these proteins, particularly HK2, as a potential treatment target for MASH.
The study, “Silencing of S100A11 attenuates murine metabolic dysfunction-associated steatohepatitis,” was published in npj Gut and Liver. The work was funded by the National Institutes of Health and Mayo Clinic.
SLD marked by abnormal buildup of liver fat
SLD is marked by the abnormal buildup of liver fat, known as steatosis. MASH is a severe form in which the buildup of liver fat triggers inflammation and scarring (fibrosis) in the liver, which can set the stage for life-threatening liver damage.
MASH is typically associated with cardiometabolic risk factors such as obesity, diabetes, and high blood levels of fatty molecules. However, the exact molecular mechanisms by which fat abnormally accumulates in the liver and drives damage remain incompletely understood. By better understanding these mechanisms, researchers hope to uncover potential targets for new treatments.
Previous studies had suggested that levels of the protein S100A11 are elevated in the liver in MASH. S100A11 is an alarmin, or a protein released when tissue is damaged, but its role in MASH is unclear.
S100A11-lacking mice fed fast food-like diet had less severe disease
To learn more, a team of scientists conducted a series of experiments using mice genetically engineered to lack S100A11. The researchers fed the mice a high-fat, high-sugar diet designed to mimic fast food, which is known to increase the risk of SLD.
In healthy mice, long-term consumption of this diet leads to MASH. But S100A11-lacking mice fed the same diet developed substantially less severe disease, with reduced steatosis and less liver inflammation and fibrosis. These mice also gained less weight, making it unclear whether the reduction in MASH severity was due to effects in the liver, or broader effects throughout the body.
To clarify this matter, the team suppressed S100A11 production specifically in the livers of healthy mice fed a fast-food diet. These mice gained weight similar to unaltered mice, but they had less steatosis, inflammation, and fibrosis — suggesting that decreasing S100A11 specifically in the liver can protect against MASH.
Genetic analyses to understand how S100A11 depletion affected liver cell activity in these mouse models revealed a dysregulation of carbohydrate and fat metabolism. Among the proteins affected by S100A11 suppression was HK2, which is for carbohydrate metabolism that “links carbohydrate to lipid [fat] metabolism,” the researchers wrote.
In both mouse and human liver samples, HK2 levels were generally low in healthy livers, but increased in MASH livers. However, liver-specific S100A11 suppression in mice lessened diet-induced HK2 increase.
Our novel observations support considering HK2 [suppression] as a potential therapeutic strategy in MASH.
The scientists next conducted experiments where they increased HK2 protein levels in mice fed a standard diet that normally doesn’t cause steatosis. Results showed that increasing HK2 levels led to steatosis in both healthy and S100A11-lacking mice.
Additional tests in lab-grown mouse liver cells indicated that exposure to palmitate, a type of saturated fat whose excessive consumption may increase the risk of SLD, boosted HK2 levels, and that this increase was lessened in the absence of S100A11.
Also, lab-grown human liver cells exposed to palmitate showed significant fat accumulation, while treatment with an HK2 blocker completely abrogated fat buildup.
“Thus, HK2 mediates palmitate-induced steatosis in [liver cells],” the researchers wrote.
Collectively, these data suggest that exposure to a fast-food-like diet can increase S100A11 activity, leading to elevated HK2 levels, which, in turn, are key for driving the buildup of fat in the liver. These data imply that these proteins, especially HK2, may be a key therapeutic target for MASH, the researchers noted.
“Our novel observations support considering HK2 [suppression] as a potential therapeutic strategy in MASH,” the team concluded.
