Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation in MASLD

Background: – Kupffer cells (KCs) are the tissue-resident macrophages of the liver, where they serve a critical role in maintaining liver tissue homeostasis and act as a filter for circulation. The composition of hepatic macrophages changes during metabolic dysfunction–associated liver disease (MASLD), with the loss of resident KCs being a hallmark of disease progression. The mechanism(s) and consequences of KC death in metabolic liver disease have yet to be defined. Transcription factor EB (TFEB) is a master regulator of lysosome function and lipid metabolism, which has been shown to protect macrophages from lipid stress in atherosclerosis. We hypothesized that TFEB would improve KC fitness in MASLD. Methods: – To investigate the potential beneficial effect of TFEB induction in KCs, we created a transgenic mouse in which TFEB was overexpressed specifically in KCs and evaluated its impact on disease pathogenesis in high-fat, high-sucrose (HFHS) and choline-deficient diet models of MASLD. Results: – We found that TFEB induction protected KCs from cell death in both models of MASLD. KC preservation through TFEB induction reduced liver steatosis with HFHS diet via mechanisms that were dependent on macrophage lysosomal lipolysis and mitochondrial fatty acid oxidation. Fibrosis was unchanged in choline-deficient diet studies. TFEB protected KCs from cell death by diminishing oxidative stress and reducing ferroptosis through a mechanism that involved enhanced NADPH levels. Conclusions: – TFEB induction promotes KC fitness upon lipid stress during MASLD. Preservation of lipid-adapted KCs demonstrates beneficial effects against liver steatosis and protects portal filtration during MASLD.