The picture shown here may illustrate an issue tha
Post# of 155654
(Total Views: 584)
Posted On: 06/12/2022 1:10:27 PM
The picture shown here may illustrate an issue that correlates well with the data we have appreciated:
https://www.nature.com/articles/s41577-021-00639-3/figures/1
It clearly shows that in NAFLD, the Hepatocyte (liver cell) itself, begins making a lot of cholesterol in the Endoplasmic Reticulum (ER), and stores it within the cell itself. There really is NO recruitment, NOR any activation of immune cells being performed in THIS stage, to any great extent.
However, in NASH, when the Hepatocytes become toxc from all the Lipids it produced, and the ER, becomes stressed and exhausted producing so much cholesterol and Lipids, that the entire cell becomes so stressed that it begins to die. Then, it exudes chemokines, and Recruits and Activates Gut Derived Cytokines & Immune cells. This leads to Inflammation which leads to fibrosis.
Now it becomes crystal clear why LL worked so much better in NASH than it did in NAFLD as apparently, there was only minimal CCR5 recruited by the Hepatocytes in NAFLD while in NASH, there was much more. And since the recruitment of these Cytokines leads to inflammation and fibrosis, it also becomes much clearer why LL was more effective in reducing fibrosis than steatosis.
It also can be understood that in the haplotype group, where CCR5 is over expressed, even at the NAFLD stage, the Hepatocytes would be expressing CCR5, more than in normal individuals, and they would begin getting expressed at less severe stages of NAS progression. So the higher dose of LL at 700 would bind and shut down the inflammatory cascade.
https://www.nature.com/articles/s41577-021-00639-3/figures/1
It clearly shows that in NAFLD, the Hepatocyte (liver cell) itself, begins making a lot of cholesterol in the Endoplasmic Reticulum (ER), and stores it within the cell itself. There really is NO recruitment, NOR any activation of immune cells being performed in THIS stage, to any great extent.
However, in NASH, when the Hepatocytes become toxc from all the Lipids it produced, and the ER, becomes stressed and exhausted producing so much cholesterol and Lipids, that the entire cell becomes so stressed that it begins to die. Then, it exudes chemokines, and Recruits and Activates Gut Derived Cytokines & Immune cells. This leads to Inflammation which leads to fibrosis.
Now it becomes crystal clear why LL worked so much better in NASH than it did in NAFLD as apparently, there was only minimal CCR5 recruited by the Hepatocytes in NAFLD while in NASH, there was much more. And since the recruitment of these Cytokines leads to inflammation and fibrosis, it also becomes much clearer why LL was more effective in reducing fibrosis than steatosis.
It also can be understood that in the haplotype group, where CCR5 is over expressed, even at the NAFLD stage, the Hepatocytes would be expressing CCR5, more than in normal individuals, and they would begin getting expressed at less severe stages of NAS progression. So the higher dose of LL at 700 would bind and shut down the inflammatory cascade.
(6)
(0)