Role of immuno-metabolic regulator LECT2 in the pathogenesis of metabolic-associated fatty liver diseases (MAFLD)

Metabolic-associated fatty liver diseases encompass a spectrum of hepatic disorders, notably non-alcoholic steatohepatitis (NASH) which is a favorable terrain for hepatocellular carcinoma (HCC) emergence. Therefore, there is an urgent need to better understand the mechanisms that trigger MAFLD progression to identify interesting molecular targets to propose innovative therapeutic strategies that remain until here very limited. We study the role of the hepatokine-like protein Leucocyte cell-derived chemotaxin 2 (LECT2) in the pathogenesis of NASH. We have previously shown that LECT2 exerts strong liver tumor-suppressive functions through its impact on macrophage polarization and function. Importantly, data also suggest that LECT2 is a key actor in metabolic disorders, as it positively correlates with BMI and waist circumference in humans. We have also demonstrated that LECT2 controls lipogenesis and cholesterol metabolism in hepatocytes in steady state. Accordingly, patients’ serum levels of LECT2 were positively correlated with steatosis. We find that LECT2 transcription is upregulated in different NAFL-inducing diet models such as High Fat High Sucrose or High Fat Diet, and NASH/HCC-inducing models such as choline-deficient high fat diet. In a LECT2-KO mouse model recreating a MAFLD phenotype using High Fat High Cholesterol diet, we show that the absence of LECT2 induces extended tissue damage, an altered inflammatory response and promotes tumor development, suggesting that LECT2 is an important factor in the microenvironment of the liver.