The 5′-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2

Abstract

The organic anion transporting polypeptides (OATPs) are important membrane proteins that mediate the cellular uptake of drugs and endogenous substances. OATP1A2 is widely distributed in many human tissues that are targeted in drug therapy; defective OATP1A2 leads to altered drug disposition influencing therapeutic outcomes. 59-AMP-activated protein kinase (AMPK) signaling plays an important role in the pathogenesis of the metabolic syndrome characterized by an increased incidence of type II diabetes and nonalcoholic fatty liver disease. This study investigated the regulatory role of AMPK in OATP1A2 transport function and expression. We found that the treatment of AMPK-specific inhibitor compound C (dorsomorphin dihydrochloride) decreased OATP1A2mediated uptake of estrone-3-sulfate in a concentration-and time-dependent manner. The impaired OATP1A2 function was associated with a reduced V max [154.6 6 17.9 pmol  (mg  4 minutes) 2 1 in compound C-treated cells vs. 413.6 6 52.5 pmol  (mg  4 minutes) 21 in controls]; the K m was unchanged. The cell-surface expression of OATP1A2 was decreased by compound C treatment, but total cellular expression was unchanged. The impaired cell-surface expression of OATP1A2 was associated with accelerated internalization and impaired targeting/recycling. Silencing of the AMPK a1-subunit using specific small interfering RNA corroborated the findings with compound C and revealed a role for AMPK in regulating OATP1A2 protein stability. Overall, this study implicated AMPK in the regulation of the function and expression of OATP1A2, which potentially impacts on the disposition of OATP1A2 drug substrates that may be used to treat patients with the metabolic syndrome and other diseases.

Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up

“…In our cohort, the presence of CA variant in SLCO1A2 rs11568563 has been strongly associated with a lower risk of DM2 incidence. These results reinforce the observations supporting the idea that gene variants in SLCO1A2 could be involved in the pathogenesis of metabolic syndrome, characterized by an increased incidence of DM2 [33].…”

Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion–transporting polypeptides

“…Interestingly, CK2 is reported to be dysregulated in many disease states, including breast cancer, in which the OATP1A2 level was elevated (42,137). Another study showed that OATP1A2 trafficking is regulated by 5'-AMP-activated protein kinase (AMPK) signaling associated with an increased incidence of type II diabetes and nonalcoholic fatty liver disease (138). Further investigations will be necessary to assess how and to what extent these multiple kinases are connected and contribute to the processing of the functional OATP1A2 in healthy and disease states.…”

Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer

“…OATP1A2 dysfunction may damage the pharmacokinetics and traits of a drug, thereby affecting the effectiveness of the treatment, and it may also hinder the absorption of endogenous organisms to the target tissue ( 43 ). OATP1A2 is regulated by AMPK, which has an impact on its membrane target, internalization, reuse, and degradation processes ( 44 ). Some researchers found that OATP1A2 could not be detected in the large intestine of normal controls when conducting intestinal transport protein research, but in another study, OATP1A2 was found to be widely expressed in patients with CRC liver metastases ( 45 , 46 ).…”