Cross-talk between gastric cancer and hepatic stellate cells promotes invadopodia formation during liver metastasis.

In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia-associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet-derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto-oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross-talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRß) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM.

circSKA3 promotes colorectal cancer metastases through miR-1238 and methylation.

Colorectal cancer (CRC) is becoming one of the most common cancers overworld, which causes a high rate of death in patients. circRNAs are non-coding RNAs(ncRNAs), which have been reported to be involved in the development of many cancers, including CRC. However, the exact mechanism that how circRNAs function through in CRC remains unclear. In this study, we firstly used GEO database and bioinformatic methods to identify the significant changed circRNAs, with circSKA3 being the most significantly upregulated circRNAs in CRC tissues. PCR results further confirmed higher expression of circSKA3 in CRC patients. CCK-8, scratch, and transwell assays indicated that circSKA3 could promote the proliferation, migration, and invasion of CRC cell lines for cell detection. Dual-luciferase assays were carried out to detect the downstream targets of circSKA3, and a binding site between circSKA3 and miR-1238 was identified and miR-1238 could also combine with YTHDF2. Overexpression of YTHDF2 rescued the decreased cell proliferation, migration, and invasion caused by miR-1238 overexpression. RIP assay further indicated that YTHDF2 could decrease the methylation of STAT5A. In summary, our study found that circSKA3 was upregulated in CRC tissues comparing with normal tissues. circSKA3 could increase the expression ofYTHDF2 through sponging miR-1238 to decrease the methylation of STAT5A, which could provide a novel target for CRC treatment.

Prediction of lymph node metastasis in T1 colorectal cancer based on combination of body composition and vascular invasion.

OBJECTIVES: Lymph node metastasis (LNM) in colorectal cancer (CRC) patients is not only associated with the tumor's local pathological characteristics but also with systemic factors. This study aims to assess the feasibility of using body composition and pathological features to predict LNM in early stage colorectal cancer (eCRC) patients. METHODS: A total of 192 patients with T1 CRC who underwent CT scans and surgical resection were retrospectively included in the study. The cross-sectional areas of skeletal muscle, subcutaneous fat, and visceral fat at the L3 vertebral body level in CT scans were measured using Image J software. Logistic regression analysis were conducted to identify the risk factors for LNM. The predictive accuracy and discriminative ability of the indicators were evaluated using receiver operating characteristic (ROC) curves. Delong test was applied to compare area under different ROC curves. RESULTS: LNM was observed in 32 out of 192 (16.7%) patients with eCRC. Multivariate analysis revealed that the ratio of skeletal muscle area to visceral fat area (SMA/VFA) (OR = 0.021, p = 0.007) and pathological indicators of vascular invasion (OR = 4.074, p = 0.020) were independent risk factors for LNM in eCRC patients. The AUROC for SMA/VFA was determined to be 0.740 (p < 0.001), while for vascular invasion, it was 0.641 (p = 0.012). Integrating both factors into a proposed predictive model resulted in an AUROC of 0.789 (p < 0.001), indicating a substantial improvement in predictive performance compared to relying on a single pathological indicator. CONCLUSION: The combination of the SMA/VFA ratio and vascular invasion provides better prediction of LNM in eCRC.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

BACKGROUND: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. METHODS: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. RESULTS: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). CONCLUSIONS: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Is total neoadjuvant treatment beneficial for locally advanced rectal cancer? a meta-analysis of randomized controlled trials.

BACKGROUND: Total neoadjuvant therapy (TNT) is a new strategy combining neoadjuvant therapy and chemotherapy to enhance tumor shrinkage and systemic control. Its effectiveness remains debated. OBJECTIVES: This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess TNT's impact and provide high-quality evidence for rectal cancer treatment decisions. METHOD: We searched China National Knowledge Infrastructure, VIP Database, Wanfang Database, China biomedical literature database, PubMed database, Embase database, and The Cochrane Library for RCTs comparing TNT with neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. The included trials were screened and assessed for quality based on inclusion and exclusion criteria, and meta-analysis was performed using RevMan 5.3 software. RESULTS: A total of 11 RCTs reported in 14 articles, with 1624 cases in the TNT group and 1541 cases in the CRT group. The results of the meta-analysis showed that compared with the CRT group, the TNT group had a higher pathological complete response rate (RR=1.65, 95% CI [1.40, 1.94], P<0.00001), higher T0 downstaging rate (RR=1.51, 95% CI [1.29, 1.77], P<0.00001), higher 3-year overall survival (HR=0.81, 95% CI [0.67, 0.98], P=0.03), and higher 3-year disease-free survival (HR=0.82, 95% CI [0.70, 0.95], P=0.008). However, there was no statistically significant difference between the two groups in terms of R0 resection rate (RR=1.02, 95% CI [0.99, 1.05], P=0.14), sphincter preservation rate (RR=0.94, 95% CI [0.88, 1.01], P=0.12), anastomotic leakage rate (RR=1.42, 95% CI [0.85, 2.38], P=0.18), and grade 3 or higher adverse events (RR=1.21, 95% CI [0.95, 1.54], P=0.13). CONCLUSIONS: In the treatment of locally advanced rectal cancer, TNT offers greater survival benefits compared to neoadjuvant CRT and does not significantly increase the incidence of adverse events. However, further data and studies with long-term outcomes are still required.

Incidence, risk factors, and predictive modeling of stoma site incisional hernia after enterostomy closure: a multicenter retrospective cohort study.

PURPOSE: Stoma site incisional hernia (SSIH) is a common complication, but its incidence and risk factors are not well known. The objective of this study is to explore the incidence and risk factors of SSIH and build a predictive model. METHODS: We performed a multicenter retrospective analysis on the patients who underwent enterostomy closure from January 2018 to August 2020. Patient's general condition, perioperative, intraoperative, and follow-up information was collected. The patients were divided into control group (no occurrence) and observation group (occurrence) according to whether SSIH occurred. Univariate and multivariate analysis were used to evaluate the risk factors of SSIH, following which we constructed a nomogram for SSIH prediction. RESULTS: One hundred fifty-six patients were enrolled in the study. The incidence of SSIH was 24.4% (38 cases), of which 14 were treated with hernia mesh repair, and the others were treated with conservative treatment. Univariate and multivariate analysis showed that age ≥ 68 years (OR 1.045, 95% CI 1.002 ~ 1.089, P = 0.038), colostomy (OR 2.913, 95% CI 1.035 ~ 8.202, P = 0.043), BMI ≥ 25 kg/m2 (OR 1.181, 95% CI 1.010 ~ 1.382, P = 0.037), malignant tumor (OR 4.838, 95% CI 1.508 ~ 15.517, P = 0.008) and emergency surgery (OR 5.327, 95% CI 1.996 ~ 14.434, P = 0.001) are the independent risk factors for SSIH. CONCLUSIONS: Based on the results, a predictive model for the occurrence of SSIH was constructed to screen high-risk groups of SSIH. For patients at high risk for SSIH, how to deal with the follow-up and prevent the occurrence of SSIH is worth further exploration.

Frizzled proteins are colonic epithelial receptors for C. difficile toxin B.

Clostridium difficile toxin B (TcdB) is a critical virulence factor that causes diseases associated with C. difficile infection. Here we carried out CRISPR-Cas9-mediated genome-wide screens and identified the members of the Wnt receptor frizzled family (FZDs) as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity towards FZD1, 2 and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signalling. FZD1/2/7 triple-knockout cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7-knockout mice, combined with knockdown of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7-knockout mice was less susceptible to TcdB-induced tissue damage in vivo. These findings establish FZDs as physiologically relevant receptors for TcdB in the colonic epithelium.

Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal human cancers. N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive. METHODS: LC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14. RESULTS: We found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells. CONCLUSIONS: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice.

MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insulin sensitivity. By small RNA-sequencing analysis, we identified seven hepatic miRNAs (including miR-29b) that are consistently aberrantly expressed across five different rodent models of metabolic dysfunction that share the feature of insulin resistance (IR). We also showed that hepatic miR-29b exhibits persistent dysregulation during disease progression in a rat model of diabetes, UCD-T2DM. Furthermore, we observed that hepatic levels of miR-29 family members are attenuated by interventions known to improve IR in rodent and rhesus macaque models. To examine the function of the miR-29 family in modulating insulin sensitivity, we used locked nucleic acid (LNA) technology and demonstrated that acute in vivo suppression of the miR-29 family in adult mice leads to significant reduction of fasting blood glucose (in both chow-fed lean and high-fat diet-fed obese mice) and improvement in insulin sensitivity (in chow-fed lean mice). We carried out whole transcriptome studies and uncovered candidate mechanisms, including regulation of DNA methyltransferase 3a (Dnmt3a) and the hormone-encoding gene Energy homeostasis associated (Enho). In sum, we showed that IR/T2D is linked to dysregulation of hepatic miR-29b across numerous models and that acute suppression of the miR-29 family in adult mice leads to improved glycemic control. Future studies should investigate the therapeutic utility of miR-29 suppression in different metabolic disease states.Enho; insulin resistance; liver; microRNA-29 (miR-29); UCD-T2DM.

Fructose and glucose can regulate mammalian target of rapamycin complex 1 and lipogenic gene expression via distinct pathways.

Although calorically equivalent to glucose, fructose appears to be more lipogenic, promoting dyslipidemia, fatty liver disease, cardiovascular disease, and diabetes. To better understand how fructose induces lipogenesis, we compared the effects of fructose and glucose on mammalian target of rapamycin complex 1 (mTORC1), which appeared to have both positive and negative effects on lipogenic gene expression. We found that fructose acutely and transiently suppressed mTORC1 signaling in vitro and in vivo The constitutive activation of mTORC1 reduced hepatic lipogenic gene expression and produced hypotriglyceridemia after 1 week of fructose feeding. In contrast, glucose did not suppress mTORC1, and the constitutive activation of mTORC1 failed to suppress plasma triglycerides after 1 week of glucose feeding. Thus, these data reveal fundamental differences in the signaling pathways used by fructose and glucose to regulate lipid metabolism.

Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse.

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2-/-), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2-/- mice are born with hepatic steatosis. Gene expression analysis in Igf2-/- newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2-/- newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

YAP suppresses gluconeogenic gene expression through PGC1α.

Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development, and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1. YAP inhibits its ability to bind to and activate transcription from the promoters of its gluconeogenic targets, and the effects of YAP are blunted upon its knockdown. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size. CONCLUSION: YAP appears to reprogram cellular metabolism, diverting substrates away from the energy-consuming process of gluconeogenesis and toward the anabolic process of growth. (Hepatology 2017;66:2029-2041).

Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation.

Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxrα in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxrα produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxrα, and LXRα was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRα to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRα and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.

Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation.

Small Heterodimer Partner (SHP) inhibits activities of numerous transcription factors involved in diverse biological pathways. As an important metabolic regulator, SHP plays a key role in maintaining cholesterol and bile acid homeostasis by inhibiting cholesterol conversion to bile acids. While SHP gene induction by increased bile acids is well established, whether SHP activity is also modulated remains unknown. Here, we report surprising findings that SHP is a rapidly degraded protein via the ubiquitin-proteasomal pathway and that bile acids or bile acid-induced intestinal fibroblast growth factor 19 (FGF19) increases stability of hepatic SHP by inhibiting proteasomal degradation in an extracellular signal-regulated kinase (ERK)-dependent manner. SHP was ubiquitinated at Lys122 and Lys123, and mutation of these sites altered its stability and repression activity. Tandem mass spectrometry revealed that upon bile acid treatment, SHP was phosphorylated at Ser26, within an ERK motif in SHP, and mutation of this site dramatically abolished SHP stability. Surprisingly, SHP stability was abnormally elevated in ob/ob mice and diet-induced obese mice. These results demonstrate an important role for regulation of SHP stability in bile acid signaling in normal conditions, and that abnormal stabilization of SHP may be associated with metabolic disorders, including obesity and diabetes.

Two cases about mesh adhesion to intra-abdominal cavity tissue after using mesh to repair an incisional hernia.

Abdominal incisional hernia is a common postoperative complication. With the development of a new type of surgical anti-adhesion mesh, mesh repair has become a widely-adopted procedure, particularly in the laparoscopic era. However, there were few reports about use of these new meshes to repair incisional hernia in the abdominal cavity. In this report, we present two cases: one a 72-year-old male and the other a 62-year-old female. Both of those patients suffered incisional hernias during abdominal operations, and therefore underwent open incisional hernia anti-adhesion mesh repair operations. Both of them had recurrent incisional hernias after the first repair operation. During the second hernia repair operation via laparoscopy, tissue from the intestine and omentum were found to have adhered seriously to the old meshes, which could cause many serious problems. We need to pay more attention to the issue of adhesion, try to determine possible reasons and improve in our future work.

[Development of Magnetic Anastomosis Device for Colostomy].

Introduction of a new magnetic anastomosis device for colostomy including its design and operaging principal. The anastomosis device is composed of magnetic base and anastomosis ring. It is convenient for colon and abdominal subcutaneous tissue going together through the magnetic attraction. The colostomy completes with magnetic compression anastomosis. The device has the advantage of making operation easer, reducing the operation steps and can better solve the colostomy ischemic necrosis, colostomy retraction, colostomy joint complications of skin mucous membrane and the skin diease around the colostomy. Patients can real y benefit from this device.

Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low-density lipoprotein receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk. Although much work is currently focused on developing therapies for inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, remains unclear. The objective of these studies was to determine the effects of insulin on PCSK9 in vitro and in vivo. APPROACH AND RESULTS: Using rat hepatoma cells and primary rat hepatocytes, we found that insulin increased PCSK9 expression and increased low-density lipoprotein receptor degradation in a PCSK9-dependent manner. In parallel, hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in mice with liver-specific knockout of the insulin receptor; 75% to 88% in mice made insulin-deficient with streptozotocin; and 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor. However, antisense oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice had little effect. In addition, we found that fasting was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling. CONCLUSIONS: Taken together, these data indicate that although insulin induces PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under all conditions.

Outbreak of Marek's disease in a vaccinated broiler breeding flock during its peak egg-laying period in China.

BACKGROUND: Outbreaks of Marek's disease (MD), caused by Marek's disease virus (MDV), primarily occur in 10-12-week-old hens. CASE PRESENTATION: We report a case of MD in a breeding flock of 24-30-week-old vaccinated broilers in China. The clinical signs in the affected chickens appeared at 24 weeks, and the incidence of tumours peaked at 30 weeks. The morbidity and mortality of the hens were 5 % and 80 %, respectively. Hematoxylin-eosin staining of the tissues showed the typical characteristics of MD. MDV infection was confirmed in the hens with an agar gel diffusion precipitation assay for the MD antigen in the feather follicle epithelium. An MDV strain, designated AH1410, was isolated from the blood lymphocytes. Sequence analyses of the pp38, meq, and gB genes revealed that strain AH1410 had molecular features consistent with a virulent, previously identified MDV. CONCLUSION: Our data provide evidence that not only is MDV becoming more virulent, but that the period of its onset in chickens is expanding. These findings provide the basis the molecular surveillance and further study of virulent MDV mutants and control strategies for MD in China.

Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins.

The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50-90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.

Early changes of microRNAs in blood one month after bariatric surgery.

BACKGROUND: Changes in microRNAs (miRNAs) are relevant to bariatric surgery and its comorbidities. The characteristics of changes in miRNAs of the early postoperative period following both bariatric procedures, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), as well as the factors that related to the effectiveness of early weight loss remain unclear. METHODS: We recruited 18 patients who performed SG and 15 patients who performed RYGB. Their preoperative and 1-month postoperative clinical data and fasting serum samples were collected, and the latter were analyzed by RNA-sequencing. Differential expression analysis of miRNAs was performed by the R-tool. Functional classification annotation and pathway enrichment analysis of targeted genes were analyzed by KOBAS software. The change profiles of miRNAs for both surgeries and their correlation with clinical characteristics and weight loss effectiveness were further analyzed. RESULTS: A total of 85 differentially expressed miRNAs were identified before and after SG, while a total of 76 were found before and after RYGB. The target genes of these miRNAs were similar in the Gene Ontology enrichment analysis in SG and RYGB, and the enrichment analysis in the Kyoto Encyclopedia of Genes and Genomes was mainly related to metabolic pathways. Hsa-miR-493-5p, hsa-miR-184, and hsa-miR-3199 exhibited similar changes in SG and RYGB, and the former two were correlated with clinical characteristics. Hsa-miR-6729-5p, hsa-miR-4659b-5p, and hsa-miR-2277-5p were correlated with the weight loss effectiveness of SG, while hsa-miR-4662a-5p was correlated with the weight loss effectiveness of RYGB. CONCLUSIONS: Short-term metabolic improvement and weight loss occurring after SG and RYGB surgery might be related to changes in miRNAs, which act on multiple biological pathways by regulating genes. In addition, some clinical characteristics and miRNAs were related to the effectiveness of early weight loss after SG and RYGB surgery. CLINICAL TRIAL REGISTRATION: ChiCTR2200058333.