LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice
Résumé
LKB1 is a “master” protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. Here it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of bile salt export pump (BSEP) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from liver-specific LKB1 knockout (LLKB1KO) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating low-density lipoprotein (LDL)- and unesterified-cholesterol levels were increased in LLKB1KO mice with an associated alteration in erythrocyte morphology and development of hyperbilirubinemia. These results indicate that LKB1 plays a critical role in bile acid homeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel, key role for LKB1 in development of hepatic morphology and membrane targeting of canalicular proteins.
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