FAM3A maintains metabolic homeostasis by interacting with F1-ATP synthase to regulate the activity and assembly of ATP synthase.

Reduced mitochondrial ATP synthase (ATPS) capacity plays crucial roles in the pathogenesis of metabolic disorders. However, there is currently no effective strategy for synchronously stimulating the expressions of ATPS key subunits to restore its assembly. This study determined the roles of mitochondrial protein FAM3A in regulating the activity and assembly of ATPS in hepatocytes. FAM3A is localized in mitochondrial matrix, where it interacts with F1-ATPS to initially activate ATP synthesis and release, and released ATP further activates P2 receptor-Akt-CREB pathway to induce FOXD3 expression. FOXD3 synchronously stimulates the transcriptions of ATPS key subunits and assembly genes to increase its assembly and capacity, augmenting ATP synthesis and inhibiting ROS production. FAM3A, FOXD3 and ATPS expressions were reduced in livers of diabetic mice and NAFLD patients. FOXD3 expression, ATPS capacity and ATP content were reduced in various tissues of FAM3A-deficient mice with dysregulated glucose and lipid metabolism. Hepatic FOXD3 activation increased ATPS assembly to ameliorate dysregulated glucose and lipid metabolism in obese mice. Hepatic FOXD3 inhibition or knockout reduced ATPS capacity to aggravate HFD-induced hyperglycemia and steatosis. In conclusion, FAM3A is an active ATPS component, and regulates its activity and assembly by activating FOXD3. Activating FAM3A-FOXD3 axis represents a viable strategy for restoring ATPS assembly to treat metabolic disorders.

Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells.

FAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet ß cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic ß cells was further examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice. In vitro, FAM3A overexpression elevated both intracellular and extracellular ATP contents and promoted PDX1 expression and insulin secretion. FAM3A-induced increase in cellular calcium (Ca2+) levels, PDX1 expression, and insulin secretion, while these were significantly repressed by inhibitors of P2 receptors or the L-type Ca2+ channels. FAM3A-induced PDX1 expression was abolished by a calmodulin inhibitor. Likewise, FAM3A-induced ß-cell proliferation was also inhibited by a P2 receptor inhibitor and an L-type Ca2+ channels inhibitor. Both intracellular and extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin secretion, and proliferation of pancreatic ß cells.

Transcriptomic landscape profiling of metformin-treated healthy mice: Implication for potential hypertension risk when prophylactically used.

Recently, the first-line anti-diabetic drug metformin shows versatile protective effects against several diseases and is potentially prescribed to healthy individual for prophylactic use against ageing or other pathophysiological processes. However, for healthy individuals, it remains unclear what effects metformin treatment will induce on their bodies. A systematic profiling of the molecular landscape of metformin treatment is expected to provide crucial implications for this issue. Here, we delineated the first transcriptomic landscape induced by metformin in 10 tissues (aorta, brown adipose, brain, eye, heart, liver, kidney, skeletal muscle, stomach and testis) of healthy mice by using RNA-sequencing technique. A comprehensive computational analysis was performed. The overrepresentation of cardiovascular disease-related gene sets, positive correlation with hypertension-related transcriptomic signatures and the associations of drugs with hypertensive side effect together indicate that although metformin does exert various beneficial effects, it would also increase the risk of hypertension in healthy mice. This prediction was experimentally validated by an independent animal experiments. Together, this study provided important resource necessary for investigating metformin's beneficial/deleterious effects on various healthy tissues, when it is potentially prescribed to healthy individual for prophylactic use.

VSMC-Specific Deletion of FAM3A Attenuated Ang II-Promoted Hypertension and Cardiovascular Hypertrophy.

RATIONALE: Dysregulated purinergic signaling transduction plays important roles in the pathogenesis of cardiovascular diseases. However, the role and mechanism of vascular smooth muscle cell (VSMC)-released ATP in the regulation of blood pressure, and the pathogenesis of hypertension remain unknown. FAM3A (family with sequence similarity 3 member A) is a new mitochondrial protein that enhances ATP production and release. High expression of FAM3A in VSMC suggests it may play a role in regulating vascular constriction and blood pressure. OBJECTIVE: To determine the role and mechanism of FAM3A-ATP signaling pathway in VSMCs in the regulation of blood pressure and the pathogenesis of hypertension. METHODS AND RESULTS: In the media layer of hypertensive rat and mouse arteries, and the internal mammary artery of hypertensive patients, FAM3A expression was increased. VSMC-specific deletion of FAM3A reduced vessel contractility and blood pressure levels in mice. Moreover, deletion of FAM3A in VSMC attenuated Ang II (angiotensin II)-induced vascular constriction and remodeling, hypertension, and cardiac hypertrophy in mice. In cultured VSMCs, Ang II activated HSF1 (heat shock factor 1) to stimulate FAM3A expression, activating ATP-P2 receptor pathway to promote the change of VSMCs from contractile phenotype to proliferative phenotype. In the VSMC layer of spontaneously hypertensive rat arteries, Ang II-induced hypertensive mouse arteries and the internal mammary artery of hypertensive patients, HSF1 expression was increased. Treatment with HSF1 inhibitor reduced artery contractility and ameliorated hypertension of spontaneously hypertensive rats. CONCLUSIONS: FAM3A is an important regulator of vascular constriction and blood pressure. Overactivation of HSF1-FAM3A-ATP signaling cascade in VSMCs plays important roles in Ang II-induced hypertension and cardiovascular diseases. Inhibitors of HSF1 could be potentially used to treat hypertension.

Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.

Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin's effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells.

So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic ß cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic ß cells using gain- and loss-of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in ß, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet ß cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A-deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and ß cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A-induced ATP release activated CaM to function as a co-activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic ß cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

FAM3C-YY1 axis is essential for TGFß-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1.

Family with sequence similarity three member C (FAM3C) (interleukin-like EMT inducer [ILEI]), heat shock factor 1 (HSF1) and Ying-Yang 1 (YY1) have been independently reported to be involved in the pathogenesis of various cancers. However, whether they are coordinated to trigger the development of cancer remains unknown. This study determined the role and mechanism of YY1 and HSF1 in FAM3C-induced proliferation and migration of breast cancer cells. In human MDA-MB-231 breast cancer cell line, transforming growth factor-ß (TGFß) up-regulated FAM3C, HSF1 and YY1 expressions. FAM3C overexpression promoted the proliferation and migration of MDA-MB-231 cells with YY1 and HSF1 up-regulation, whereas FAM3C silencing exerted the opposite effects. FAM3C inhibition repressed TGFß-induced HSF1 activation, and proliferation and migration of breast cancer cells. YY1 was shown to directly activate HSF1 transcription to promote the proliferation and migration of breast cancer cells. YY1 silencing blunted FAM3C- and TGFß-triggered activation of HSF1-Akt-Cyclin D1 pathway, and proliferation and migration of breast cancer cells. Inhibition of HSF1 blocked TGFß-, FAM3C- and YY1-induced proliferation and migration of breast cancer cells. YY1 and HSF1 had little effect on FAM3C expression. Similarly, inhibition of HSF1 also blunted FAM3C- and TGFß-promoted proliferation and migration of human breast cancer BT-549 cells. In human breast cancer tissues, FAM3C, YY1 and HSF1 protein expressions were increased. In conclusion, FAM3C activated YY1-HSF1 signalling axis to promote the proliferation and migration of breast cancer cells. Furthermore, novel FAM3C-YY1-HSF1 pathway plays an important role in TGFß-triggered proliferation and migration of human breast cancer MDA-MB-231 cells.

FAM3B (PANDER) functions as a co-activator of FOXO1 to promote gluconeogenesis in hepatocytes.

FAM3B, also known as PANcreatic DERived factor (PANDER), promotes gluconeogenesis and lipogenesis in hepatocytes. However, the underlying mechanism(s) still remains largely unclear. This study determined the mechanism of PANDER-induced FOXO1 activation in hepatocytes. In mouse livers and cultured hepatocytes, PANDER protein is located in both the cytoplasm and nucleus. Nuclear PANDER distribution was increased in the livers of obese mice. In cultured mouse and human hepatocytes, PANDER was co-localized with FOXO1 in the nucleus. PANDER directly interacted with FOXO1 in mouse and human hepatocytes. PANDER overexpression enhanced PANDER-FOXO1 interaction, and detained FOXO1 in the nucleus upon insulin stimulation in hepatocytes. With the increase in PANDER-FOXO1 interaction, PANDER overexpression upregulated the expression of gluconeogenic genes and promoted gluconeogenesis in both human and mouse hepatocytes. Luciferase reporter assays further revealed that PANDER augmented the transcriptional activity of FOXO1 on gluconeogenic genes. Moreover, PANDER overexpression also interfered the binding of AS1842856, a specific FOXO1 inhibitor, with FOXO1, and impaired its inhibitory effects on gluconeogenic gene expression and gluconeogenesis in hepatocytes. siRNA mediated-silencing of FOXO1 inhibited PANDER-promoted gluconeogenic gene expression and glucose production in hepatocytes. In conclusion, PANDER protein is abundantly present in the nucleus, where it functions as a new co-activator of FOXO1 to induce gluconeogenic gene expression in hepatocytes.

Defining Essentiality Score of Protein-Coding Genes and Long Noncoding RNAs.

Measuring the essentiality of genes is critically important in biology and medicine. Here we proposed a computational method, GIC (Gene Importance Calculator), which can efficiently predict the essentiality of both protein-coding genes and long noncoding RNAs (lncRNAs) based on only sequence information. For identifying the essentiality of protein-coding genes, GIC outperformed well-established computational scores. In an independent mouse lncRNA dataset, GIC also achieved an exciting performance (AUC = 0.918). In contrast, the traditional computational methods are not applicable to lncRNAs. Moreover, we explored several potential applications of GIC score. Firstly, we revealed a correlation between gene GIC score and research hotspots of genes. Moreover, GIC score can be used to evaluate whether a gene in mouse is representative for its homolog in human by dissecting its cross-species difference. This is critical for basic medicine because many basic medical studies are performed in animal models. Finally, we showed that GIC score can be used to identify candidate genes from a transcriptomics study. GIC is freely available at http://www.cuilab.cn/gic/.

Metformin Alters Gut Microbiota of Healthy Mice: Implication for Its Potential Role in Gut Microbiota Homeostasis.

In recent years, the first-line anti-diabetic drug metformin has been shown to be also useful for the treatment of other diseases like cancer. To date, few reports were about the impact of metformin on gut microbiota. To fully understand the mechanism of action of metformin in treating diseases other than diabetes, it is especially important to investigate the impact of long-term metformin treatment on the gut microbiome in non-diabetic status. In this study, we treated healthy mice with metformin for 30 days, and observed 46 significantly changed gut microbes by using the 16S rRNA-based microbiome profiling technique. We found that microbes from the Verrucomicrobiaceae and Prevotellaceae classes were enriched, while those from Lachnospiraceae and Rhodobacteraceae were depleted. We further compared the altered microbiome profile with the profiles under various disease conditions using our recently developed comparative microbiome tool known as MicroPattern. Interestingly, the treatment of diabetes patients with metformin positively correlates with colon cancer and type 1 diabetes, indicating a confounding effect on the gut microbiome in patients with diabetes. However, the treatment of healthy mice with metformin exhibits a negative correlation with multiple inflammatory diseases, indicating a protective anti-inflammatory role of metformin in non-diabetes status. This result underscores the potential effect of metformin on gut microbiome homeostasis, which may contribute to the treatment of non-diabetic diseases.

Phosphorus-32 interstitial radiotherapy for recurrent craniopharyngioma: Expressions of vascular endothelial growth factor and its receptor-2 and imaging features of tumors are associated with tumor radiosensitivity.

To investigate the relationship of the expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR-2) and imaging features with the therapeutic efficacy of Phosphorus-32 colloid interstitial radiotherapy in recurrent craniopharyngioma.Thirty-two patients with recurrent craniopharyngioma underwent phosphorus-32 colloid interstitial radiotherapy. The tumor imaging features were classified into 4 types according to the thickness of the cyst wall and signals of the cyst contents as shown by computed tomography (CT) and magnetic resonance imaging (MRI) images. Protein expressions of VEGF and VEGFR-2 in craniopharyngioma tissues were evaluated with immunohistochemistry before radiotherapy. The tumor radiosensitivity was determined at 12 months after the interstitial radiotherapy.VEGF mainly expressed in the tumor cytoplasm, and VEGFR-2 expressed either in vascular endothelial cells or in tumor endothelial cells. VEGF/VEGFR-2 expressions varied significantly in cases sensitive or insensitive to the radiotherapy (VEGF: P = .028; VEGFR-2: P = .017). Tumor imaging features were associated with the therapeutic efficacy of interstitial radiotherapy (P = .000). VEGF expression had no association with the imaging features of tumors (P = .226), but VEGFR-2 expression was associated with the imaging features of tumors (P = .008).Our results confirmed the association among imaging features, VEGFR-2 expressions, and tumor radiosensitivity in craniopharyngiomas. Imaging features and VEGFR-2 expressions may add useful data to the radiosensitive assessment of craniopharyngiomas.

Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver.

Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis.

Mammalian genomes encode a huge number of long noncoding RNAs (lncRNAs) with unknown functions. This study determined the role and mechanism of a new lncRNA, lncRNA suppressor of hepatic gluconeogenesis and lipogenesis (lncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and patients with nonalcoholic fatty liver disease, the expression levels of mouse lncSHGL and its human homologous lncRNA B4GALT1-AS1 were reduced. Hepatic lncSHGL restoration improved hyperglycemia, insulin resistance, and steatosis in obese diabetic mice, whereas hepatic lncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. lncSHGL overexpression increased Akt phosphorylation and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas lncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, lncSHGL recruited heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) to enhance the translation efficiency of CALM mRNAs to increase calmodulin (CaM) protein level without affecting their transcription, leading to the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway and repression of the mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated the CaM/Akt pathway and repressed the mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, lncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating the lncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) and diabetes are severe public health issues worldwide. The Family with sequence similarity 3 (FAM3) gene family consists of four members designated as FAM3A, FAM3B, FAM3C and FAM3D, respectively. Recently, there had been increasing evidence that FAM3A, FAM3B and FAM3C are important regulators of glucose and lipid metabolism. FAM3A expression is reduced in the livers of diabetic rodents and NAFLD patients. Hepatic FAM3A restoration activates ATP-P2 receptor-Akt and AMPK pathways to attenuate steatosis and hyperglycemia in obese diabetic mice. FAM3C expression is also reduced in the liver under diabetic condition. FAM3C is a new hepatokine that activates HSF1-CaM-Akt pathway and represses mTOR-SREBP1-FAS pathway to suppress hepatic gluconeogenesis and lipogenesis. In contrast, hepatic expression of FAM3B, also called PANDER, is increased under obese state. FAM3B promotes hepatic lipogenesis and gluconeogenesis by repressing Akt and AMPK activities, and activating lipogenic pathway. Under obese state, the imbalance among hepatic FAM3A, FAM3B and FAM3C signaling networks plays important roles in the pathogenesis of NAFLD and type 2 diabetes. This review briefly discussed the latest research progress on the roles and mechanisms of FAM3A, FAM3B and FAM3C in the regulation of hepatic glucose and lipid metabolism.

FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice.

FAM3C, a member of FAM3 gene family, has been shown to improve insulin resistance and hyperglycemia in obese mice. This study further determined whether FAM3C functions as a hepatokine to suppress hepatic gluconeogenesis of type 1 diabetic mice. In STZ-induced type 1 diabetic mouse liver, the FAM3C-HSF1-CaM signaling axis was repressed. Hepatic FAM3C overexpression activated HSF1-CaM-Akt pathway to repress gluconeogenic gene expression and ameliorate hyperglycemia of type 1 diabetic mice. Moreover, hepatic HSF1 overexpression also activated CaM-Akt pathway to repress gluconeogenic gene expression and improve hyperglycemia of type 1 diabetic mice. Hepatic FAM3C and HSF1 overexpression had little effect on serum insulin levels in type 1 diabetic mice. In cultured hepatocytes, conditioned medium of Ad-FAM3C-infected cells induced Akt phosphorylation. Moreover, Akt activation and gluconeogenesis repression induced by FAM3C overexpression were reversed by the treatment with anti-FAM3C antibodies. Treatment with recombinant FAM3C protein induced Akt activation in a HSF1- and CaM-dependent manner in cultured hepatocytes. Furthermore, recombinant FAM3C protein repressed gluconeogenic gene expression and gluconeogenesis by inactivating FOXO1 in a HSF1-dependent manner in cultured hepatocytes. In conclusion, FAM3C is a new hepatokine that suppresses hepatic gluconeogenic gene expression and gluconeogenesis independent of insulin by activating HSF1-CaM-Akt pathway.

MeSAUR1, Encoded by a Small Auxin-Up RNA Gene, Acts as a Transcription Regulator to Positively Regulate ADP-Glucose Pyrophosphorylase Small Subunit1a Gene in Cassava.

Cassava, being one of the top three tuberous crops, features highly efficient starch accumulation in the storage root to adapt the tropical resources and environments. The molecular mechanism for the process, however, is still unclear. ADP-glucose pyrophosphorylase, the first and rate-limited enzyme in starch biosynthesis pathway, is a heterotetramer comprised of two small/catalytic and two large/modulatory subunits. To understand the regulation of MeAGPase, the promoter of a highly expressed small subunit, MeAGPs1a, was used as bait for a yeast one-hybrid assay to screen storage root cDNA library. One cDNA, coding for a small auxin-up RNA protein, named MeSAUR1, was isolated from cassava. MeSAUR1 could bind to the promoter of MeAGPS1a in yeast one-hybrid test and in vitro, and was located in cell nucleus. MeSAUR1 displayed a higher transcript level in cassava root cortex, and its expression was induced by indole-3-acetic acid, gibberellin and ethylene, but repressed by abscisic acid. A dual-luciferase interaction test further convinced that MeSAUR1 could bind to the promoter of MeAGPS1a, and positively regulate the transcription of MeAGPS1a in cassava.

FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress.

FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone's beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARγ agonist(s) on liver IRI are dependent on FAM3A-ATP-Akt pathway.

NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.

Hepatic FAM3A expression is repressed under obese conditions, but the underlying mechanism remains unknown. This study determined the role and mechanism of miR-423-5p in hepatic glucose and lipid metabolism by repressing FAM3A expression. miR-423-5p expression was increased in the livers of obese diabetic mice and in patients with nonalcoholic fatty liver disease (NAFLD) with decreased FAM3A expression. miR-423-5p directly targeted FAM3A mRNA to repress its expression and the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic miR-423-5p inhibition suppressed gluconeogenesis and improved insulin resistance, hyperglycemia, and fatty liver in obese diabetic mice. In contrast, hepatic miR-423-5p overexpression promoted gluconeogenesis and hyperglycemia and increased lipid deposition in normal mice. miR-423-5p inhibition activated the FAM3A-ATP-Akt pathway and repressed gluconeogenic and lipogenic gene expression in diabetic mouse livers. The miR-423 precursor gene was further shown to be a target gene of NFE2, which induced miR-423-5p expression to repress the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic NFE2 overexpression upregulated miR-423-5p to repress the FAM3A-ATP-Akt pathway, promoting gluconeogenesis and lipid deposition and causing hyperglycemia in normal mice. In conclusion, under the obese condition, activation of the hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing the FAM3A-ATP-Akt signaling pathway.

Epithelioid inflammatory myofibroblastic sarcoma in abdominal cavity: a case report and review of literature.

In this study, we present a rare and difficult case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) in abdominal cavity. A 47-year-old female presented as left upper abdominal pain for 6 months and abdominal distention for 1 month. CT examination showed a solid mass in the left upper intra-abdomen. Grossly, the tumor was found in the mesenterium of colon with the size of 7.5 × 6.5 × 3.5 cm, and was solid and gray-yellowish in the cut surface. Focal myxomatous appearance was observed. Microscopically, stromal myxoid change together with prominant infiltrated lymphocytes, neutrophils and eosinophils were found in the tumor, and the tumor cells were round, epithelioid with vesicular nuclei, large prominant nucleoli and high mitotic rate. Immunohistochemically, strong diffused positive for vimentin, desmin, ALK (nuclear membrane staining pattern) and AAT, focally positive for CD99 and CD30, were showed, Ki67 index was about 20%; Especially, WT-1 and D240 were focally expressed in this tumor. FISH analysis showed rearrangement of ALK, and reverse-transcription polymerase chain reaction (RT-PCR) analysis was used to detect the fusion location of the RANBP2 and ALK gene. The diagnosis of EMIS was made based on its location, typical morphology, the immunohistochemical features especially the nuclear membranous immunostaining of ALK and rearrangement of RANBP2-ALK. The tumor showed higher aggressive behaviors and a poor prognosis. The differential diagnosis and other treatments of EMIS are also discussed in the present study. This finding may increase the case information of EMIS.

[Leukoencephalopathy with cerebral calcification and cysts: a case report and review of literature].

OBJECTIVE: To improve the diagnostic ability of leukoencephalopathy with cerebral calcifications and cysts (LCC), a rare central nervous system disease. METHODS: The clinical manifestations, neuroimages and neuropathological features of a 19-year-old male patient were analyzed. A total of 20 cases from 14 literatures were reviewed. RESULT: The patient was admitted with right limb weakness, cognitive decline, headache and blurred eyesight. Head CT scan showed multiple calcifications, cysts formation and leukoencephalopathy. Brain MRI showed several cysts in bilateral hemisphere, basal ganglia, thalamus and paraventricular areas. A mural nodule was noted inside one of the cyst, which was enhanced on the contrasted MRI. The wall of the cysts was partially enhanced, but not with the fluid inside the cysts. The corresponding CT calcifications foci showed on T1 and T2 with either both hyperintensity or both hypointensity, which was also partial enhanced. Extensive leukoencephalopathy was formed around the cysts and the ventricles. But neither Cho nor NAA changed a lot on MRS. Amplitude diagram of SWI series exhibited multiple round small dark signals all over the affected areas with mixed signals showed in the phase diagram, which indicated both calcifications and microbleeding at the lesions. Neuropathological examinations found no tumor cells in the operated cyst, and showed angiomatous small blood cells were dominant in the cyst wall. Hyaline degenerations, microcalcifications and hemosiderin deposition were observed. No obvious demyelination was discovered, while gliosis, numerous Rosenthal fibers and fibrinoid vascular necrosis were found around the lesions. The clinical, neuroimaging and pathological features of this patient were in accordance with the cases reported in the literatures. CONCLUSIONS: Neuroimaging is the most important method for the diagnosis of LCC. As small vessel lesions are probably closely related to the pathophysiology of LCC, SWI could be recommended to further reveal the etiology of LCC.