Liver cells protect themselves using a sugar mechanism
Not all immune cells in the liver do the same job.
The liver contains two types of cells called macrophages. The first type, known as Kupffer cells, are present from embryonic development onward. They keep the liver healthy and guard against inflammation. The second type arrives from circulating blood cells and invades the liver during disease. This second type actually contributes to damage.
Chi3l1 as a key regulator
In metabolic dysfunction-associated steatotic liver disease (MASLD), also known as metabolic fatty liver disease, the protective Kupffer cells are gradually displaced by the damaging blood-derived macrophages. Why this happens was unclear. The researchers, publishing in eLife, identified a protein called Chi3l1 (chitinase 3-like 1) as a key player.
That protein directly binds glucose (blood sugar) and thereby inhibits its uptake into the cell. Kupffer cells are strongly dependent on glucose as an energy source. When Chi3l1 is active, those cells are protected from metabolic stress. Without Chi3l1, Kupffer cells die off more rapidly under metabolic stress, allowing the damaging macrophages to take over, substantially worsening liver disease.
Cell type-specific effect
Notably, this effect is cell type-specific. The blood-derived macrophages are less glucose-dependent and barely affected by Chi3l1. That makes the protein a potentially attractive therapeutic target: an intervention targeting Chi3l1 in Kupffer cells could, in theory, preserve the protective cells without strengthening the harmful ones.
The study was conducted in mice. Whether the findings apply to humans with MASLD requires follow-up research. Metabolic liver disease is one of the fastest-growing liver conditions worldwide, driven in part by rising rates of obesity and type 2 diabetes.
Search terms: hepatic macrophages MASLD metabolic regulation, Kupffer cells glucose metabolism liver disease, Chi3l1 macrophage cell survival