Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis
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Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased KCTD17 levels in patients with MASH, and in dietary rodent models of MASH—such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, l-amino acid-defined, high-fat diet—which showed an inverse correlation with the expression of serine protease inhibitor a3k (SERPINA3 in humans, Serpina3k in mice). KCTD17 depletion increased SERPINA3 levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates Serpina3k expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased KCTD17 levels in patients with MASH, and in dietary rodent models of MASH—such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, l-amino acid-defined, high-fat diet—which showed an inverse correlation with the expression of serine protease inhibitor a3k (SERPINA3 in humans, Serpina3k in mice). KCTD17 depletion increased SERPINA3 levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates Serpina3k expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.