Abstract Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most common liver disease worldwide. The progression to fibrosis, occurring against a backdrop of hepatic steatosis and inflammation, critically determines liver-related morbidity and mortality. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as a strategy to mitigate liver fibrosis. Lipopolysaccharide binding protein (LBP) is a secreted protein that plays an established role in innate immune responses. Here, using adoptive transfer studies and tissue-specific deletion models we show that hepatocytes are the dominant contributors to circulating LBP. In a murine model of MAFLD, hepatocyte-specific deletion of LBP restrained hepatic inflammation and improved liver function abnormalities, but not measures of fibrosis. Human studies, including genetic evidence, corroborate an important role for LBP in hepatic inflammation with minimal impact on fibrosis. Collectively, our data argues against the idea that targeting hepatic inflammation is a viable approach to reducing fibrosis.

Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD