BSEP is a member of the ABC (ATP-binding-cassette) transporter family and is classified as ABCB11 (ABC subfamily B, member 11). For example, the polar nature of hepatocytes allows the efficient vectorial transport of bile acids from the portal blood into the hepatocytes via NTCP and then into the intrahepatic biliary system via BSEP (bile salt export pump). A major feature of hepatocytes is their marked anatomical polarity, which plays an essential role in their function. Completion of the enterohepatic circulation occurs when the bile acids are returned to the liver mainly by transport via NTCP (sodium–taurochloate co-transporting protein). The majority of the bile acids are then returned to the liver via the portal circulation through ASBT (apical sodium-dependent bile acid transporter) in the epithelial cells of the small intestine. Following their synthesis in the liver, bile acids are secreted into the bile, stored in the gall bladder and released postprandially into the small intestine, where they play a critical role in the absorption of fat and fat-soluble nutrients. Because high levels of bile acids can cause tissue damage due to their strong detergent properties, their concentrations are tightly regulated by transcriptional control of many genes in a complex feedback mechanism involving bile acid activation of FXR (farnesoid X receptor) (reviewed in ). Bile is the main vehicle by which the body disposes of excess cholesterol by conversion into bile acids and the route used for the excretion of waste products such as bilirubin, a breakdown product of haem. The liver has many metabolic functions including bile production together with key regulatory roles in glucose, lipid and xenobiotic metabolism. Information concerning the physiological function of the remaining AMPK-related kinases is extremely limited. Much less is understood regarding the roles of the AMPK-related kinases, although there is evidence to suggest that the MARK and BRSK (brain-specific kinase) subfamilies play roles in determining cell polarity. Activation of AMPK by LKB1 under conditions of energy depletion results in the down-regulation of energy-consuming pathways and the up-regulation of ATP-producing pathways. LKB1 phosphorylates a conserved threonine residue within the T-loop of these kinases, which is essential for their activation. More recently, LKB1 has been shown to act upstream of AMPK (AMP-activated protein kinase) and 12 AMPK-related kinases. LKB1 encodes an evolutionarily conserved serine/threonine protein kinase that was originally identified as a tumour suppressor, as inactivating mutations in LKB1 in humans cause Peutz–Jeghers syndrome. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive.
Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. 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. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. However, the long-term role of LKB1 in hepatic function is unknown. LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis.
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