Dataset Information

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis.

ABSTRACT:

Background

Organic cation transporters (OCT) are responsible for the uptake of a broad spectrum of endogenous and exogenous substrates. Downregulation of OCT is frequently observed in human hepatocellular carcinoma (HCC) and is associated with a poor outcome. The aim of our current study was to elucidate the impact of OCT3 on hepatocarcinogenesis.

Methods

Transcriptional and functional loss of OCT was investigated in primary murine hepatocytes, derived from Oct3-knockout (Oct3^-/-; FVB.Slc22a3^tm1Dpb ) and wildtype (WT) mice. Liver tumors were induced in Oct3^-/- and WT mice with Diethylnitrosamine and Phenobarbital over 10 months and characterized macroscopically and microscopically. Key survival pathways were investigated by Western Blot analysis.

Results

Loss of Oct3^-/- in primary hepatocytes resulted in significantly reduced OCT activity determined by [³H]MPP⁺ uptake in vivo. Furthermore, tumor size and quantity were markedly enhanced in Oct3^-/- mice (p<0.0001). Oct3^-/- tumors showed significant higher proliferation (p<0.0001). Ki-67 and Cyclin D expression were significantly increased in primary Oct3^-/- hepatocytes after treatment with the OCT inhibitors quinine or verapamil (p<0.05). Functional inhibition of OCT by quinine resulted in an activation of c-Jun N-terminal kinase (Jnk), especially in Oct3^-/- hepatocytes.

Conclusion

Loss of Oct3 leads to enhanced proliferation and hepatocarcinogenesis in vivo.

SUBMITTER: Vollmar J

PROVIDER: S-EPMC5777802 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis.

Vollmar Johanna J Lautem Anja A Closs Ellen E Schuppan Detlef D Kim Yong Ook YO Grimm Daniel D Marquardt Jens U JU Fuchs Peter P Straub Beate K BK Schad Arno A Gründemann Dirk D Schattenberg Jörn M JM Gehrke Nadine N Wörns Marcus A MA Baumgart Jan J Galle Peter R PR Zimmermann Tim T

Oncotarget 20171218 70

<h4>Background</h4>Organic cation transporters (OCT) are responsible for the uptake of a broad spectrum of endogenous and exogenous substrates. Downregulation of OCT is frequently observed in human hepatocellular carcinoma (HCC) and is associated with a poor outcome. The aim of our current study was to elucidate the impact of OCT3 on hepatocarcinogenesis.<h4>Methods</h4>Transcriptional and functional loss of OCT was investigated in primary murine hepatocytes, derived from Oct3-knockout (Oct3<sup ...[more]

PMID: 29383190

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Project description:Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced β-adrenergic receptor (β-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of β-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs β-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders.

Project description:The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 microM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.

Dataset Information

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis.

Background

Methods

Results

Conclusion

Publications

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis.

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