Nonalcoholic fatty liver disease (NAFLD) is very common; as many as 25 percent of adults around the world are impacted by the disorder. In NAFLD, liver cells die, damaging the organ. NALFD can also progress to a more severe form in which cell death accelerates, which can cause scarring in the liver and cirrhosis. Several new studies have revealed more about the progression of NAFLD to NASH.
In one study from scientists at Penn State, a mechanism potentially driving the progression of NAFLD to NASH was identified. The findings were reported in Science Translational Medicine.
In this study, the researchers used a mouse model; some mice were fed normal mouse food while others got an American-style diet that is thought to induce obesity, including foods that are high in sugars, fats, and processing. The researchers performed single-cell sequencing on over 28,000 mouse liver cells, comparing those from mice eating normal mouse food to those on the American diet. This work revealed that some liver cells or hepatocytes were expressing Ephrin type B receptor 2 (EphB2), a protein that is not usually active in hepatocytes.
Additional research indicated that signaling involving the Notch pathway in adjacent cells was leading to the activation of EphB2. This activity caused inflammation to develop in the liver.
The investigators were also able to obtain human liver cells from NAFLD patients, and they found that EphB2 was also being expressed in those cells. The researchers suggested that the production of EphB2 is likely linked to the progression of NAFLD to NASH. Therapeutics that aim to decrease or halt EphB2 activity may help treat the disease.
In NAFLD, hepatocytes die, which causes liver damage. If the disease progresses to NASH, hepatocyte death increases even more. In a different report published in Nature Communications, scientists at Kanazawa University used an obese mouse model to reveal that mild fatty liver leads to a cell death process called apoptosis, while severe fatty liver causes another type of cell death called necroptosis. The two processes differ because in apoptosis, inflammation doesn't happen; apoptotic cells shrink down but their membrane tends to stay intact, so the process doesn't usually affect other cells. But in necroptosis, the rupture of cells leads to inflammation and more cell death.
It had been thought that necroptosis does not happen in hepatocytes, because the process is mediated by RIPK3, a regulator that is not particularly active in liver cells. The investigators revealed, however, that hepatocytes increase RIPK3 levels as fat builds up in the liver. The mode of cell death then changes from apoptosis to necroptosis.
The researchers halted the expression of RIPK3 using siRNA in their mouse model. This showed that the death of liver cells and liver damage was minimized once RIPK3 was no longer expressed, even in animals with severe fatty liver. The expression of a transcription factor called ATF3 was closely linked to RIPK3 activity, and the study suggested that ATF3 is involved with the switch from apoptosis to necroptosis in NASH. Previous work by this group has identified eIF2α signaling as a player in fatty liver cell death.
In yet another study, also reported in Nature Communications, researchers discovered that the absence of a gene called SRSF1 caused a mouse model to develop the signs of NASH. This study has suggested that without SRSF1, DNA becomes damaged in cells, which then stop functioning correctly. This causes fat to build up, because the SRSF1-deficient liver cells are no longer packaging it properly. The dead cells aren't moved away, and inflammation sets in, followed by scarring and fibrosis.
"Liver cells are encountering toxins and DNA damage more than any other cells in our body. This study illustrates that when liver cells encounter excessive DNA damage, these NASH symptoms develop. SRSF1 plays a protective role against that. It acts as a guardian of the liver genome," said study leader Auinash Kalsotra, a professor at the University of Illinois at Urbana-Champaign.
Hopefully, all of these studies will lead to better animal models for NASH, and potential treatments for the disease. A recent study has also shown that fasting and exercise can be simple but effective ways to reduce NAFLD symptoms.
Sources: Science Translational Medicine, Kanazawa University, Yuka Inaba et al Nature Communications 2023, University of Illinois at Urbana-Champaign, Wagar Arif et al Nature Communications 2023
