Modulation of mitochondrial dynamism in Kupffer cells impacts systemic metabolism

Background: Kupffer cells (KCs) are hepatoresident macrophages that are essential for liver physiology and contribute to the development of nonalcoholic hepatic steatosis (NAFLD). The liver of patients with MAFLD shows different expressions of some key regulators of inner mitochondrial membrane fusion compared with healthy subjects, including OPA1 protein, which is a mitochondrial protein whose activity promotes mitochondrial fusion and modulation of oxidative phosphorylation. Aims: Given the close interaction that KCs have with cells in the hepatic niches, they play both a crucial immune and metabolic role, which is why their mitochondria are critical for their function. This project aims to investigate how modulation of OPA1-driven mitochondrial fusion in KCs can affect lipid metabolism and immune response at the systemic and hepatic levels. Methods: Mice selectively lacking OPA1 in the KCs were fed a Standard Diet or a High Fat Diet for 20 weeks. The immune phenotype was assessed by cytofluorimetry while the metabolic profile by in vivo indirect calorimetry and with plasma and tissue lipid profile analysis. Single cell RNA sequencing was also performed to profile the impact of OPA1 deficiency on KC function and possible paracrine effects on hepatocytes. Results: Under standard dietary conditions, mice selectively lacking OPA1 in KCs show a different metabolic substrate preference compared to wild type, with an immunophenotype characterized by a higher proportion of pro-resolution KC2 than pro-inflammatory KC1. Functionally, KCs also exhibit dissimilar phagocytic and proliferative capacity. During the high-fat diet, we observed a significant reduction in liver fibrosis. Conclusions: Taken together, these data suggest that OPA1 plays a key role in the function of Kupffer cells and that the lack of OPA1, causing metabolic reprogramming, affects their interaction with resident liver cells, influencing the development of fibrosis and the progression of MAFLD.