The fight against nonalcoholic steatohepatitis (NASH), a severe form of liver disease known as non-alcoholic fatty liver disease (NAFLD), affecting about 20-30% of people worldwide, has seen a significant breakthrough with the discovery of the beneficial effects of a compound called 15-keto-PGE2. NASH leads to excessive fat build-up in the liver and can result in serious conditions like liver scarring and even cancer if untreated. A major cause of this disease is obesity, often due to diets high in fat, which worsens the condition by increasing harmful oxidative stress and resistance to insulin in the liver.
Professor Lee-Ming Chuang from National Taiwan University, along with his team, has been at the forefront of this research, shedding light on the notable findings related to 15-keto-PGE2, an agent known for reducing inflammation. “15-keto-PGE2 brings about changes in specific components of NF-kB, a group of proteins that play a key role in controlling inflammation, specifically targeting the components p105/p50 and p65. This leads to a reduction in NF-kB’s ability to drive inflammatory processes in immune cells known as macrophages,” explained Professor Chuang. This finding suggests that 15-keto-PGE2 can effectively reduce inflammation in the liver.
In studies conducted on mice models, the results of treating with 15-keto-PGE2 were significant. “In mice with NASH, caused by a long-term diet high in fat and sugar, treatment with 15-keto-PGE2 notably reduced liver inflammation and lowered the levels of ALT and AST, enzymes that indicate liver damage. It also reduced the presence of macrophages, which are immune cells involved in inflammation,” Professor Chuang emphasized. This points to the potential of 15-keto-PGE2 in halting the advancement of liver inflammation.
Delving deeper, Professor Chuang stated, “In mice placed on a high-fat and high-sugar diet for three months, treatment with 15-keto-PGE2 consistently decreased fasting blood sugar levels and the levels of inflammatory substances. Also, in mice fed this diet for ten months, which led to the development of liver disease, a six-week treatment with 15-keto-PGE2 reduced liver damage.” These improvements were seen in the levels of ALT and AST, a reduction in macrophage activation, and a decrease in the size of fat deposits in the liver.
The study highlights the crucial role of NF-kB, a group of proteins, in controlling liver inflammation and its activation in the progression of liver diseases like NAFLD. Through specific tests, the study confirmed that 15-keto-PGE2 attaches to NF-kB components in macrophages and liver tissues. “By influencing the Rel homology domain (RHD) of p65, a part of NF-kB, 15-keto-PGE2 is able to prevent p65 from entering the nucleus, thereby reducing the activation of the NF-kB pathway, which is known to cause inflammation,” further explained Professor Chuang.
In conclusion, the research on 15-keto-PGE2 opens new doors for the treatment of NASH, a growing global health concern. Its proven effectiveness in reducing liver inflammation and improving overall liver health presents 15-keto-PGE2 as a potential new treatment option for the millions of people affected by this condition worldwide.
Journal Reference
Siow-Wey Hee, Yi-Cheng Chang, Lynn Su, Daniel Liao, Shiau-Mei Chen, Lee-Ming Chuang et al. “15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors.” iScience (2023). DOI: https://doi.org/10.1016/j.isci.2023.107997.
