Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is a serious threat to public health, but its underlying mechanism remains poorly understood. In screening important genes using Gene Importance Calculator (GIC) we developed previously, ribosomal modification protein rimK-like family member A (RIMKLA) was predicted as one essential gene but its functions remained largely unknown. The current study determined the roles of RIMKLA in regulating glucose and lipid metabolism. RIMKLA expression was reduced in livers of human and mouse with NAFLD. Hepatic RIMKLA overexpression ameliorated steatosis and hyperglycemia in obese mice. Hepatocyte-specific RIMKLA knockout aggravated high-fat diet (HFD)-induced dysregulated glucose/lipid metabolism in mice. Mechanistically, RIMKLA is a new protein kinase that phosphorylates betaine-homocysteine S-methyltransferase 1 (BHMT1) at threonine 45 (Thr45) site. Upon phosphorylation at Thr45 and activation, BHMT1 eliminated homocysteine (Hcy) to inhibit the activity of transcription factor activator protein 1 (AP1) and its induction on fatty acid synthase (FASn) and cluster of differentiation 36 (CD36) gene transcriptions, concurrently repressing lipid synthesis and uptake in hepatocytes. Thr45 to alanine (T45A) mutation inactivated BHMT1 to abolish RIMKLA's repression on Hcy level, AP1 activity, FASn/CD36 expressions, and lipid deposition. BHMT1 overexpression rescued the dysregulated lipid metabolism in RIMKLA-deficient hepatocytes. In summary, RIMKLA is a novel protein kinase that phosphorylates BHMT1 at Thr45 to repress lipid synthesis and uptake. Under obese condition, inhibition of RIMKLA impairs BHMT1 activity to promote hepatic lipid deposition.

PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis.

BACKGROUND: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet ß cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed. METHODS: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays. RESULTS: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers. CONCLUSIONS: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.

Mesenteric Lymphatic B Cells Migrate to the Intestine and Aggravate DSS-Induced Colitis via the CXCR5-CXCL13 Axis.

The pathogenesis of inflammatory bowel disease (IBD) is still unknown. Mesenteric lymphatics (MLs), which are closely related to the intestine in both anatomy and physiology, have been suggested to be involved in IBD. In the present study, we aim to investigate the effects of ML immune cells on IBD and explore the potential associated mechanisms. Acute colitis was induced in rats using dextran sulfate sodium salt (DSS). Mesenteric lymphangiogenesis, ML stenosis, and dilation were observed, with an increased proportion of MLB cells in DSS-induced colitis rats. The adoptive transfer of B cells isolated from ML (MLB) was employed to investigate their effects on colitis. MLB cells derived from DSS-induced colitis rats exhibited a higher propensity to migrate to the intestine. The proportion of colonic T cells was altered, along with the aggravated colitis induced by the adoptive transfer of MLB cells derived from DSS-induced colitis rats. RNA sequencing revealed increased Cxcr5 expression in MLB cells from colitis rats, while real-time PCR indicated an upregulation of its ligand Cxcl13 in the colon of colitis rats. These findings suggest that MLB cells may migrate to the intestine and aggravate colitis. In summary, colonic T cells respond to MLB cells from colitis rats, and MLB cells aggravate DSS-induced colitis via the CXCR5-CXCL13 axis.

Serum uric acid levels and prognosis of patients with non-alcoholic fatty liver disease.

Uric acid (UA) is associated with non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether UA plays a predictive role in NAFLD prognosis. This study aimed to explore the relationship between UA levels and mortality in NAFLD patients without severe renal disease. Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES). Time-dependent Cox regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for mortality. Overall, 2493 individuals with NAFLD and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were included in this study. The median follow-up period was 26.58 years. Patients were divided into high and low-UA groups according to UA levels. Time-independent Cox regression showed that UA level was not an independent risk factor for mortality in NAFLD patients without decreased eGFR (P > 0.05). After matching for age and sex using the propensity score matching method, UA remained not independently associated with death in NAFLD patients (P > 0.05). Similar results were found for cardiovascular-related and cancer-related deaths. Although UA is closely related to NAFLD, UA levels are not independently associated with the long-term survival of patients with NAFLD without decreased eGFR.

Hepatocyte-secreted FAM3D ameliorates hepatic steatosis by activating FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide; however, the underlying mechanisms remain poorly understood. FAM3D is a member of the FAM3 family; however, its role in hepatic glycolipid metabolism remains unknown. Serum FAM3D levels are positively correlated with fasting blood glucose levels in patients with diabetes. Hepatocytes express and secrete FAM3D, and its expression is increased in steatotic human and mouse livers. Hepatic FAM3D overexpression ameliorated hyperglycemia and steatosis in obese mice, whereas FAM3D-deficient mice exhibited exaggerated hyperglycemia and steatosis after high-fat diet (HFD)-feeding. In cultured hepatocytes, FAM3D overexpression or recombinant FAM3D protein (rFAM3D) treatment reduced gluconeogenesis and lipid deposition, which were blocked by anti-FAM3D antibodies or inhibition of its receptor, formyl peptide receptor 1 (FPR1). FPR1 overexpression suppressed gluconeogenesis and reduced lipid deposition in wild hepatocytes but not in FAM3D-deficient hepatocytes. The addition of rFAM3D restored FPR1's inhibitory effects on gluconeogenesis and lipid deposition in FAM3D-deficient hepatocytes. Hepatic FPR1 overexpression ameliorated hyperglycemia and steatosis in obese mice. RNA sequencing and DNA pull-down revealed that the FAM3D-FPR1 axis upregulated the expression of heterogeneous nuclear ribonucleoprotein U (hnRNP U), which recruits the glucocorticoid receptor (GR) to the promoter region of the short-chain acyl-CoA dehydrogenase (SCAD) gene, promoting its transcription to enhance lipid oxidation. Moreover, FAM3D-FPR1 axis also activates calmodulin-Akt pathway to suppress gluconeogenesis in hepatocytes. In conclusion, hepatocyte-secreted FAM3D activated the FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation in hepatocytes. Under obesity conditions, increased hepatic FAM3D expression is a compensatory mechanism against dysregulated glucose and lipid metabolism.

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.

Imipramine activates FAM3A-FOXA2-CPT2 pathway to ameliorate hepatic steatosis.

Mitochondrial FAM3A has been revealed to be a viable target for treating diabetes and nonalcoholic fatty liver disease (NAFLD). However, its distinct mechanism in ameliorating hepatic steatosis remained unrevealed. High-throughput RNA sequencing revealed that carnitine palmityl transferase 2 (CPT2), one of the key enzymes for lipid oxidation, is the downstream molecule of FAM3A signaling pathway in hepatocytes. Intensive study demonstrated that FAM3A-induced ATP release activated P2 receptor to promote the translocation of calmodulin (CaM) from cytoplasm into nucleus, where it functioned as a co-activator of forkhead box protein A2 (FOXA2) to promote the transcription of CPT2, increasing free fatty acid oxidation and reducing lipid deposition in hepatocytes. Furthermore, antidepressant imipramine activated FAM3A-ATP-P2 receptor-CaM-FOXA2-CPT2 pathway to reduce lipid deposition in hepatocytes. In FAM3A-deficient hepatocytes, imipramine failed to activate CaM-FOXA2-CPT2 axis to increase lipid oxidation. Imipramine administration significantly ameliorated hepatic steatosis, hyperglycemia and obesity of obese mice mainly by activating FAM3A-ATP-CaM-FOXA2-CPT2 pathway in liver and thermogenesis in brown adipose tissue (BAT). In FAM3A-deficient mice fed on high-fat-diet, imipramine treatment failed to correct the dysregulated lipid and glucose metabolism, and activate thermogenesis in BAT. In conclusion, imipramine activates FAM3A-ATP-CaM-FOXA2-CPT2 pathway to ameliorate steatosis. For depressive patients complicated with metabolic disorders, imipramine may be recommended in priority as antidepressive drug.

ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism.

Diabetes (DM), especially type 2 diabetes (T2DM) has become one of the major diseases severely threatening public health worldwide. Islet beta cell dysfunctions and peripheral insulin resistance including liver and muscle metabolic disorder play decisive roles in the pathogenesis of T2DM. Particularly, increased hepatic gluconeogenesis due to insulin deficiency or resistance is the central event in the development of fasting hyperglycemia. To maintain or restore the functions of islet beta cells and suppress hepatic gluconeogenesis is crucial for delaying or even stopping the progression of T2DM and diabetic complications. As the key energy outcome of mitochondrial oxidative phosphorylation, adenosine triphosphate (ATP) plays vital roles in the process of almost all the biological activities including metabolic regulation. Cellular adenosine triphosphate participates intracellular energy transfer in all forms of life. Recently, it had also been revealed that ATP can be released by islet beta cells and hepatocytes, and the released ATP and its degraded products including ADP, AMP and adenosine act as important signaling molecules to regulate islet beta cell functions and hepatic glycolipid metabolism via the activation of P2 receptors (ATP receptors). In this review, the latest findings regarding the roles and mechanisms of intracellular and extracellular ATP in regulating islet functions and hepatic glycolipid metabolism would be briefly summarized and discussed.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .

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.

Y/X-Chromosome-Bearing Sperm Shows Elevated Ratio in the Left but Not the Right Testes in Healthy Mice.

The sex chromosomes play central roles in determining the sex of almost all of the multicellular organisms. It is well known that meiosis in mammalian spermatogenesis produces ~50% Y- and ~50% X-chromosome-bearing sperm, a 1:1 ratio. Here we first reveal that the X-chromosome-encoded miRNAs show lower expression levels in the left testis than in the right testis in healthy mice using bioinformatics modeling of miRNA-sequencing data, suggesting that the Y:X ratio could be unbalanced between the left testis and the right testis. We further reveal that the Y:X ratio is significantly elevated in the left testis but balanced in the right testis using flow cytometry. This study represents the first time the biased Y:X ratio in the left testis but not in the right testis is revealed.

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.

Long Non-Coding RNA in the Pathogenesis of Cancers.

The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

Mesenteric lymph node CD4+ T lymphocytes migrate to liver and contribute to non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by altered intestinal microbiota and intestinal immune disorder. Here we investigated the role of mesenteric lymph node (MLN) CD4+ T lymphocytes in NAFLD. In high fat diet (HFD)-fed mice, the percentage ratios of Th1 to Th2 cells and Th17 to Treg cells were imbalanced in MLNs. Co-culture assays showed MLN CD4+ T lymphocytes from HFD-fed mice tended to migrate to the liver and promoted hepatic inflammation. Adoptive transfer of MLN CD4+ T lymphocytes from NAFLD mice to HFD-fed mice resulted in higher transaminase, worse hepatic inflammation and lipid accumulation. Antibiotics and probiotics were administrated to regulate intestinal microbiota, and the restoration of MLN Th1/Th2 and Th17/Treg cells in alleviated NAFLD were found. In summary, MLNs CD4+ T subtype cells may involve in NAFLD, and the restoration of MLN CD4+ T subtype cells ratio by regulating intestinal bacteria could be the new strategies.

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non-alcoholic fatty liver disease mice.

Mesenteric adipose tissue (MAT) inflammation is associated with non-alcoholic fatty liver disease (NAFLD), and immune cells play pivotal roles in the inflammation of adipose tissue. Here, we investigated the roles of MAT B lymphocytes in NAFLD. Mice fed with high-fat diet (HFD) and normal diet (ND) were killed in time gradients (4, 8 and 12 weeks). Compared with ND-fed mice, intra-hepatic CD45+ CD19+ B lymphocytes increased after 4 weeks (P < 0.01) of HFD feeding, and lasted until the 12th week, infiltrated earlier than CD45+ CD3+ T lymphocytes and CD45+ F4/80+ macrophages. The mRNA expression of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 decreased in MAT of Bnull HFD-fed mice compared to that in wild-type HFD-fed mice, along with lesser macrophages. Mesenteric adipose tissue B cells from HFD-fed mice promoted macrophage differentiation to type-Ι macrophages and expression of pro-inflammatory cytokines in vitro. Macrophages pre-treated with MAT B cells from HFD-fed mice showed elevated mRNA expression of IL-6 and TNF-α and declined IL-10 levels in adipocytes compared to ND MAT B cell pre-treated macrophages. Besides, internal near-infrared scanning and external transwell assay showed that HFD MAT B cells migrated to the liver more than ND MAT B cells. High-fat diet MAT B cells induced higher MCP-1 and lower IL-10 expression in primary hepatocytes compared to ND MAT B cells in co-culture experiment. These data indicate that B lymphocytes infiltrate early in MAT during the development of NAFLD, which may not only promote MAT inflammation by regulating macrophages but also migrate to the liver and induce hepatocytes inflammation.

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.

Mesenteric adipose tissue contributes to intestinal barrier integrity and protects against nonalcoholic fatty liver disease in mice.

Visceral adipose tissue (VAT) is related to nonalcoholic fatty liver disease (NAFLD). However, the role of mesenteric adipose tissue (MAT), part of the VAT, in NAFLD is unclear. In the present study, we monitored the liver and four depots of the VAT in high-fat diet (HFD)-feeding mice at multiple time points (4, 8, and 12 wk). The MAT had become inflamed by the eighth week of HFD feeding, earlier than other depots of VAT. Furthermore, MAT removal after 8 wk of HFD resulted in more severe steatosis and more foci of inflammation infiltration, as well as higher NAFLD activity scores. Consistent with these findings, the mRNA expression of proinflammatory cytokines and lipid anabolism genes was increased in the livers of inflamed MAT-removal mice. MAT removal also injured the intestinal barrier and promoted intestinal inflammation. The bacterial load translocated to the liver and circulating levels of lipopolysaccharide were also evaluated in inflamed MAT-removal mice. In a coculture experiment involving adipocytes and intestinal epithelial cells, mRNA expression of zonula occludens-1 (ZO-1), and occludin in CT-26 cells was upregulated and permeability of monolayer Caco-2 cells was elevated under stimulation from adipocytes or inflamed adipocytes. Taken together, these results demonstrated that MAT removal damaged the intestinal barrier and aggravated NAFLD and that MAT inflammation may be a compensatory response to protect the liver by maintaining the intestinal barrier. NEW & NOTEWORTHY The mesenteric adipose tissue (MAT) lies between the gut and liver and plays a critical role in hepatic metabolic diseases. In the present study, we found that the MAT was prone to inflammation in high-fat diet-fed mice. Removal of the inflamed MAT resulted in more hepatic inflammation, lipid accumulation, and decreased glucose tolerance. Furthermore, we showed that the MAT contributed to intestinal barrier integrity, thus clarifying why MAT removal aggravated nonalcoholic fatty liver disease.

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.

FAM3A enhances adipogenesis of 3T3-L1 preadipocytes via activation of ATP-P2 receptor-Akt signaling pathway.

FAM3A plays important roles in regulating hepatic glucose/lipid metabolism and the proliferation of VSMCs. This study determined the role and mechanism of FAM3A in the adipogenesis of 3T3-L1 preadipocytes. During the adipogenesis of 3T3-L1 preadipocytes, FAM3A expression was significantly increased. FAM3A overexpression enhanced 3T3-L1 preadipocyte adipogenesis with increased phosphorylated Akt (pAkt) level, whereas FAM3A silencing inhibited 3T3-L1 preadipocyte adipogenesis with reduced pAkt level. Moreover, FAM3A silencing reduced the expression and secretion of adipokines in 3T3-L1 cells. FAM3A protein is mainly located in mitochondrial fraction of 3T3-L1 cells and mouse adipose tissue. FAM3A overexpression increased, whereas FAM3A silencing decreased ATP production in 3T3-L1 preadipocytes. FAM3A-induced adipogenesis of 3T3-L1 preadipocytes was blunted by inhibitor of P2 receptor. In white adipose tissues of db/db and HFD-fed obese mice, FAM3A expression was reduced. One-month rosiglitazone administration upregulated FAM3A expression, and increased cellular ATP content and pAkt level in white adipose tissues of normal and obese mice. In conclusion, FAM3A enhances the adipogenesis of preadipocytes by activating ATP-P2 receptor-Akt pathway. Under obese condition, a decrease in FAM3A expression in adipose tissues plays important roles in the development of adipose dysfunction and type 2 diabetes.