李于：SIRT1 ReguLATion of Energy Metabolism: Attenuation of Hepatic Steatosis and Obesity
Fibroblast growth factor 21 (FGF21) is the hepatocyte-derived hormone that reguLATes fatty acid metabolism and has potential to treat obesity and diabetes. We recently indicate that hepatic overexpression of SIRT1 in diabetic mice attenuates hepatic steatosis and insulin resistance. However, the in vivo long-term consequence of hepatic SIRT1 abLATion in liver physiology remains unknown.
We showed that hepatocyte-specific SIRT1 knockout (SIRT1 LKO) mice with the albumin Cre-loxP system exhibited a striking phenotype with greater propensity for obesity on a chow diet, characterized by increased whole body mass and fat mass, reduced energy expenditure, and unaltered food intake and physical activity. The obese phenotypes of SIRT1 LKO mice were associated with reduced hepatic and circuLATing levels of fasting FGF21.
Hepatic impairment of FGF21 repressed expression of key enzymes involving fatty acid oxidation such as CPT1α and MCAD, and inhibited expression of ketogenic enzymes including ACAT1, HMGCS2, HMGCL, and BDH1, thereby reducing plasma β–hydroxybutyrate levels in SIRT1 LKO mice. Moreover, transcriptional activity of a FGF21 promoter-driven luciferase reporter was stimuLATed by SIRT1 activators, resveratrol and SRT1720, in SIRT1+/+ MEFs, but not in SIRT1-/- MEFs.
The ability of resveratrol and SRT1720 to stimuLATe FGF21 protein was abolished by SIRT1 H335A inactive mutant or by nicotinamide and splitomicin in HepG2 cells. Induction of FGF21 by SIRT1 activators enhanced expression of key enzymes for fatty acid oxidation and ketogenesis.
These in vivo and in vitro findings characterize 1) hepatic SIRT1 as a master reguLATor of FGF21; 2) SIRT1-dependent activation of FGF21 in liver as a component for adaptive fasting response; and 3) defective hepatic SIRT1 and FGF21 signaling as a key pathological determinant of energy metabolic abnormality and obesity susceptibility.
贾立军：NeddyLATion蛋白修饰-CRL 泛素连接酶通路调控肿瘤细胞自噬应答的机制与潜在应用
贾立军博士，复旦大学附属肿瘤医院肿瘤研究所研究员和博士生导师。目前主要从事“针对蛋白质翻译后修饰通路进行抗肿瘤分子靶点发现”等研究工作。
相关研究在 J Natl Cancer Inst（JNCI）、Cancer Research、Clinical Cancer Research、Autophagy、Cell Death & Differentiation、Cell Death & Disease、Int J Cancer和J Biol Chem等学术期刊发表文章40篇、获邀参编英文专著4部。主持国家自然科学基金（81372196，31071204，30500637，81172092）、国家重大科学研究计划（2012CB910302，课题负责）、上海市卫生局A类重点项目 (2010012)、上海市“浦江人才 ”资助计划（12PJ1400600）和上海高校特聘教授（东方学者）资助计划等科研项目。
学术兼职包括：国家自然科学基金委员会医学科学领域学科评审组专家、中华医学科技奖评审委员会委员、上海市免疫学会肿瘤免疫专业委员会委员、高等学校自然科学奖和技术发明奖评审专家和十余种学术期刊审稿专家。荣获上海高校特聘教授（东方学者）和上海市浦江人才等荣誉称号。
秦正红：DRAM1 reguLATes autophagy flux and Bid-mediated cell death via lysosomes
秦正红，博士，教授，神经药理专业博士生导师。1994年在美国宾州医学院研究生院获博士学位，先后在美国国家卫生研究院(NIH)及麻省总医院和哈佛大学医学院从事研究工作。2003年从哈佛大学引进，现为苏州大学医学部基础医学与生物科学学院科研中心实验室主任，中国药理学会生化药理学专业委员会委员，中国药理学会神经药理学专业委员会委员，美国神经科学学会会员。
Damage-reguLATed autophagy moduLATor1 (DRAM1), a novel TP53 target gene, is an evolutionarily conserved lysosomal protein and plays an essential role in TP53-dependent autophagy activation and apoptosis (Crighton et al, 2006). However, the mechanisms by which DRAM1 promotes autophagy and apoptosis are not clear.
3-Nitropropionic acid (3-NP) is an inhibitor of mitochondrial respiratory complex II. Intrastriatal administration of 3-NP produces neuropathology resemble to Huntington disease. 3-NP-induced neuronal death was involved in autophagy and apoptosis. In vitro studies with 3-NP in TP53 wt and null cells, 3-NP or CCCP increased the protein levels of DRAM1 in a TP53-dependent or independent manner. DRAM1 induction contributed to 3-NP-induced autophagy activation. Knock-down of DRAM1 with siRNA inhibited the activity of V-ATPase, acidification of lysosomes and activation of lysosomal proteases. Knock-down of DRAM1 reduced the clearance of autophagososmes.
3-NP also induced a transcription independent upreguLATion of BAX protein levels. Knock-down of DRAM1 suppressed the increase in BAX levels. Co-immunoprecipitation and pull-down studies revealed an interaction of DRAM1 and BAX protein. Stably expression of exogenous DRAM1 increased the half-life of BAX. UpreguLATion of DRAM1 recruited BAX to lysosomes and induced cathepsin B-dependent cleavage of Bid and cytochrome c release. Knockdown of DRAM1, BAX or inhibition of lysosomal enzymes reduced 3-NP-induced cytochrome c release and cell death.
These data suggest that DRAM1 plays important roles in reguLATing autophagy flux and apoptosis. DRAM1 promotes autophagy flux through a mechanism involves activation of V-ATPase and enhances the acidification of lysosomes. DRAM1 promotes apoptosis via a mechanism involving recruitment of BAX to lysosomes to trigger cathepsin B-mediated Bid cleavage.
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