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The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders.

Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1(-/-) A(y)/a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the Arnt promoter in MIN6 cells. These results suggest that in mouse pancreatic islets mRNA expression of Arnt fluctuates significantly in a circadian manner and that the down-regulation of Dbp and up-regulation E4bp4 contribute to direct suppression of Arnt expression in diabetes.

56歳，女性が３年前に胃mucosa-associated lymphoid tissue (MALT) リンパ腫と診断された．Helicobacter pylori (HP) 陽性であり除菌を施行されたが不成功でありその後は経過観察されていた．２年後に右眼瞼腫瘤を指摘され生検にてMALTリンパ腫と診断され，胃ではMALTリンパ腫の増大，肺の浸潤影を認めた．胃MALTリンパ腫の生検では瀰漫性のリンパ球の浸潤および一部には形質細胞への分化を認めた．血清中の単クローン性IgM，λの増加，骨髄では形質細胞の浸潤を認めた．HPに対して２次除菌を行い成功した．次いでrituximabとcladribine (2-chlorodeoxyadenosine，2CdA) の併用，R-2CdA療法を４コース施行しMALTリンパ腫は縮小しIgMは減少したが正常値にはならなかったのでCHOP療法２コースを追加しIgMはさらに減少した．MALTリンパ腫における長期間にわたる多様な臨床経過に対し注意深い観察および必要な時に適切な治療を行うことが必要である．

72歳，男性が発熱，腰痛，全身倦怠感を訴えて来院した．患者は６年前に他院にて瀰漫性大細胞型B細胞性リンパ腫と診断され化学療法にて寛解に導入されたが，５年後リンパ腫は再発し再度の化学療法にて部分寛解に導入された．当院初診時の検査所見では貧血，LDH，sIL-2Rの著増，D-dimerの増加を認めた．骨髄穿刺，骨髄生検にて壊死細胞のみ採取された．MRIでは脊椎椎体はT1で巣状にlow intensityを呈した．感染症は否定的であった．これらの症状および検査所見は骨髄壊死に特徴的でありリンパ腫の再燃により合併したと考えられた．CHOP,R-CHOP,THP-COPなどの化学療法を開始したところ一時的に血液像は改善し，骨髄穿刺は可能になり造血細胞も少数認められた．しかし最終的には効果はなく約３ヵ月後に多臓器不全にて死亡した．剖検ではリンパ腫の進展，リンパ腫細胞の骨髄への浸潤および多発性の骨髄壊死が認められた．骨髄壊死の発症の機序としてはリンパ腫細胞の骨髄浸潤，DIC,炎症性サイトカインなどの関与が示唆された．

A 68-year-old female complained of anemia and bone pain. Monoclonal increase of plasma IgA, lambda-type was observed, and immature plasma cells were detected in the bone marrow. These plasma cells showed intermediate differentiation on CD38 gating flow cytometry. Chromosomal analysis demonstrated complex abnormalities including repeats and translocation, t(8;22)(q24;q11.2) by G-banding, and breakpoint down stream of 3'c-MYC on fluorescence in situ hybridization. Multiple myeloma with variant type translocation was diagnosed. Treatment with continuous infusion of dexamethasone and oral administration of thalidomide effectively decreased IgA, plasma cells and chromosomal abnormality, facilitating complete remission.