Surplus fatty acid synthesis increases oxidative stress in adipocytes and lnduces lipodystrophy.

Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Ceramide d18:1/24:1 as a potential biomarker to differentiate obesity subtypes with unfavorable health outcomes.

BACKGROUND: The criteria for metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) remain controversial. This research aimed to identify a potential biomarker to differentiate the subtypes of obesity. METHODS: The study conducted a lipidomic evaluation of ceramide in the serum of 77 Chinese adults who had undergone hyperinsulinemic-euglycemic clamps. These adults were divided into three groups according to the clinical data: normal weight control group (N = 21), MHO (N = 20), and MUO (N = 36). RESULTS: The serum Cer d18:1/24:1 level in the MHO group was lower than that in the MUO group. As the Cer d18:1/24:1 level increased, insulin sensitivity decreased, and the unfavorable parameters increased in parallel. Multivariate logistic regression analysis revealed that serum Cer d18:1/24:1 levels were independently correlated with MUO in obesity. Individuals with higher levels of Cer d18:1/24:1 also had an elevated risk of cardiovascular disease. Most ceramide subtype levels increased in obesity compared to normal-weight individuals, but the levels of serum Cer d18:0/18:0 and Cer d18:1/16:0 decreased in obesity. CONCLUSIONS: The relationships between ceramide subtypes and metabolic profiles might be heterogeneous in populations with different body weights. Cer d18:1/24:1 could be a biomarker that can be used to differentiate MUO from MHO, and to better predict who will develop unfavorable health outcomes among obese individuals. TRIAL REGISTRATION: The First Affiliated Hospital of Nanjing Medical University's Institutional Review Board authorized this study protocol, and all participants provided written informed consent (2014-SR-003) prior to study entry.

Genetic analysis and functional study of a novel ABCG5 mutation in sitosterolemia with hematologic disease.

Sitosterolemia is a rare autosomal recessive hereditary disease caused by loss-of-function genetic mutations in either ATP-binding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8). Here, we investigate novel variants in ABCG5 and ABCG8 that are associated with the sitosterolemia phenotype. We describe a 32-year-old woman with hypercholesterolemia, tendon and hip xanthomas, autoimmune hemolytic anemia and macrothrombocytopenia from early life, which make us highly suspicious of the possibility of sitosterolemia. A novel homozygous variant in ABCG5 (c.1769C>A, p.S590X) was identified by genomic sequencing. We also examined the lipid profile, especially plant sterols levels, using gas chromatography-mass spectrometry. Functional studies, including western blotting and immunofluorescence staining, showed that the nonsense mutation ABCG5 1769C>A hinders the formation of ABCG5 and ABCG8 heterodimers and the function of transporting sterols. Our study expands the knowledge of variants in sitosterolemia and provides diagnosis and treatment recommendations.

Diagnosis and genetic analysis of a case with glycogen storage disease type V caused by compound heterozygous mutations in the PYGM gene.

Glycogen storage disease type V is an autosomal recessive genetic disorder caused by muscle glycogen phosphorylase (PYGM) deficiency, which is characterized by exercise intolerance, second wind phenomena and high level of serum creatine kinase. In this study, we reported a Chinese young man with glycogen storage disease type V, with lower extremity weakness after exercise, increased creatine kinase, and slight fat infiltration in the posterior group of thigh muscle by magnetic resonance imaging (MRI). The proband had complex heterozygous PYGM disease-causing mutations, including c.308T>C (p.L103P) variant transmitted from the mother and c.260_261delCT (p.S87Ffs*23) from the father, of which the former was a novel PYGM mutation. This study enriched the PYGM pathogenic gene mutation spectrum, contributed to improve clinicians' understanding of glycogen storage disease type V and provided a reference for further genetic study of the disease.

Rare Diseases in Glycosphingolipid Metabolism.

Sphingolipidoses is a cluster of genetic rare disorders regarding glycosphingolipid metabolism, classified as lysosomal storage disorders (LSD). Here, we focus on eight inheritable diseases, including GM1 gangliosidosis, GM2 gangliosidosis, Fabry disease, Gaucher's disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease A and B, and Farber disease. Mostly, pathogenic mutations in the key enzyme are loss-function, resulting in accumulation of substrates and deficiency of products. Thus, cellular overload of substrates causes lipotoxicity, which is deleterious to cellular and organ function. In the terms of clinical manifestations in sphingolipidoses, multiple systems and organs, especially central nervous system (CNS) are usually affected. As for diagnosis strategy, enzymatic activity assay and genetic sequencing are helpful. Up till now, limited treatment approaches have approved for treating sphingolipidoses, with some potential strategies for further evaluation. In general, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and molecular chaperones are feasible choices for enzyme deficiency disorders, but these therapies are limited to relieve CNS lesions and symptoms due to prevention from blood-brain barrier. Other possible treatments such as gene therapy, bone marrow transplantation (BMT), and hematopoietic stem cell transplantation (HSCT) need further evaluation.

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles.

OBJECTIVE: To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS: In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS: All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; ß = -0.335, P = 0.004) and taurodeoxycholic acid (TDCA; ß = -0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (ß = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS: Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

Progress on familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal inherited disease characterized by a significant increase in low density lipoprotein cholesterol (LDL-C), tendon xanthoma and premature coronary artery disease (PCAD). In this paper, we analyze the current research status of FH, summarize the reported mutation gene loci in Chinese FH patients and treatment for them, and elaborate the current status of patents and drug researches. The results show that scientific outcomes of FH are increasing with a good developmental trend and the most popular topics of FH study are pathogenesis, treatment of FH, and research on juvenile FH patients. In terms of patents, large pharmaceutical companies, such as Regeneron Pharmaceuticals Inc, AstraZeneca Plc, Merck & Co Inc, are actively engaged in FH detection, diagnosis and treatment. In addition, 12 drugs have been launched in the United States, Japan, Europe and other countries or regions, bringing hope to FH patients.

Current status and future perspectives of rare disease research.

Rare diseases refer to diseases with low incidence. Currently, there are over 8000 rare diseases in the world. Effective prevention and treatment of rare diseases is an important part of 'healthy China'. In this paper, status and drug development of rare diseases were reported. These results indicate that research on rare diseases is growing rapidly driven by technology and policy. The hotspots include the identification of gene mutations, the development of therapies, and the key points of technology include the development of drugs for rare diseases, the development of viral vectors for gene therapy, and the diagnosis and management system for rare diseases. In terms of drug development, 880 drugs have been launched by December 28, 2020, and a large number of drugs are in the pre-clinical stage. Generally, a new technology or drug is applicable to various diseases. In the future, with policy support and the development of emerging technologies such as gene editing, more and more rare diseases will be diagnosed and intervened early, even be cured, and the quality of life of patients is expected to be improved.

Targeted lipidomics reveals associations between serum sphingolipids and insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp.

AIMS: Sphingolipids(SPs) and their substrates and constituents, fatty acids (FAs), are implicated in the pathogenesis of various metabolic diseases associated. This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. METHODS: We conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults using LC/MS. The glucose infusion rate over 30 min (GIR30) was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value. RESULTS: Total and subspecies of serum SMs and globotriaosyl ceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (areas under the curve > 0.80) based on GIR30 as standard diagnostic criteria, and (SM/Cer)/(BMI*LDLc) areas under the curve = 0.93) is the best. CONCLUSIONS: These results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp and identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

Effectiveness of companion-intensive multi-aspect weight management in Chinese adults with obesity: a 6-month multicenter randomized clinical trial.

BACKGROUND: Obesity is a globally increasing health epidemic requiring early lifestyle intervention. Our main objective was to examine the effectiveness of companion-intensive multi-aspect weight management (CIMWM) in Chinese adults with obesity. METHODS: In this 6-month, prospective, open-label, multicenter, randomized controlled clinical trial, we recruited 272 obese adults aged 18-50 years with a body mass index (BMI) ≥ 28.0 kg/m2 and capable of using smartphones. CIMWM (n = 136) offered both daily online instructions and monthly face-to-face guidance by physicians, dietitians, and health managers along with the provision of meal replacements in the first 3 months. Traditional multi-aspect weight management (TMWM, n = 136) provided monthly face-to-face guidance by the same panel of professionals and the same meal replacements as CIMWM group, but required subjects to complete daily self-monitoring instead of offering daily online instructions. Body composition and metabolic parameters were assessed at baseline, 1, 2, 3, and 6 months by physicians. The primary outcomes were clinically-significant weight loss and changes in BMI and body composition. RESULTS: Participants in both groups showed significantly reduced BMI, body fat mass (BFM), visceral fat area (VFA), and HOMA-IR (p < 0.05). CIMWM was shown to be superior to TMWM in the improvement of clinically-significant weight loss, BMI, total cholesterol (TC), the body composition parameters BFM and the skeletal muscle mass-to-visceral fat area ratio (S/V) (p < 0.05). The non-alcoholic fatty liver disease score (NFS) was negatively related to S/V at baseline. After weight management, NFS was lowered among individuals with levels in the highest tertile (p < 0.05). Metabolic memory in terms of the continuous reduction of BMI, BFM, and TC was retained up to 6 months in spite of participants transferring to self-monitoring assessment in the final 3 months. CONCLUSIONS: The CIMWM strategy in obese Chinese adults is proved to be more effective than TMWM in weight loss, and motivates greater adherence to intervention and lifestyle reprogramming. Trial registration Chinese Clinical Trial Registry, ChiCTR1800017463, Registered July 31, 2018. http://www.chictr.org.cn/showproj.aspx?proj=29649 .

Relationship between Serum Indirect Bilirubin Level and Insulin Sensitivity: Results from Two Independent Cohorts of Obese Patients with Impaired Glucose Regulation and Type 2 Diabetes Mellitus in China.

BACKGROUND: Serum bilirubin is an endogenous antioxidant that has protective effects against obesity-related metabolic diseases. OBJECTIVES: This study aimed to evaluate the characteristics of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) and their relationships with insulin sensitivity in obese patients with impaired glucose regulation and type 2 diabetes mellitus (IGR/T2DM) in China. Patients and Methods. Cohort 1 comprised obese patients (n = 71) was divided into the IGR/T2DM group (n = 38, obesity with IGR/T2DM) and control group (n = 33, obesity without IGR/T2DM). Insulin sensitivity was evaluated using the hyperinsulinemic-euglycemic clamp technique (HEC) with glucose disposal rate (GDR, M value). Cohort 2 comprised obese patients with IGR/T2DM who underwent metabolic surgery (n = 109) as complementary to cohort 1. Insulin sensitivity was evaluated with the Matsuda Index and homeostatic model assessment of insulin sensitivity (HOMA-IS). RESULTS: In cohort 1, TBIL, DBIL, and IBIL were higher within the physiological range in the IGR/T2DM group compared with the control group; IBIL was positively correlated with M value (r = 0.342, p=0.044) in the IGR/T2DM group, and multivariate logistic regression showed that IBIL might be independent protective factors against insulin resistance (odds ratio (OR) = 0.602; 95% confidence interval (CI): 0.413-0.878; p=0.008). In cohort 2, at 1 month after metabolic surgery, serum bilirubin levels (TBIL, DBIL, and IBIL) increased, and the percentage change in IBIL was positively correlated with the change of the Matsuda Index (r = 0.195, p=0.045). CONCLUSIONS: The relationships between different types of bilirubin and insulin sensitivity varied. Serum indirect bilirubin might be a protective factor that enhances insulin sensitivity.

Rare Diseases Related with Lipoprotein Metabolism.

Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on common diseases. One of the most famous milestones made by Michael Brown and Joseph Goldstein in metabolism field is the discovery of the defective gene in familial hypercholesterolemia, a rare human genetic disease manifested with extreme high level of serum cholesterol (Goldstein JL, Brown MS, Proc Natl Acad Sci USA 70:2804-2808, 1973; Brown MS, Dana SE, Goldstein JL, J Biol Chem 249:789-796, 1974). Follow-up work including decoding the gene function, mapping-related pathways, and screening therapeutic targets are all based on the primary finding (Goldstein JL, Brown MS Arterioscler Thromb Vasc Biol 29:431-438, 2009). A series of succession win the two brilliant scientists the 1985 Nobel Prize, and bring about statins widely used for lipid management and decreasing cardiovascular disease risks. Translating the clinical extreme phenotypes into laboratory bench work has turned out to be the first important step in the paradigm conducting translational and precise medical research. Here we review the main categories of rare disorders related with lipoprotein metabolism, aiming to strengthen the notion that human rare inheritable genetic diseases would be the window to know ourselves better, to treat someone more efficiently, and to lead a healthy life longer. Few rare diseases related with lipoprotein metabolism were clustered into six sections based on changes in lipid profile, namely, hyper- or hypocholesterolemia, hypo- or hyperalphalipoproteinemia, abetalipoproteinemia, hypobetalipoproteinemia, and sphingolipid metabolism diseases. Each section consists of a brief introduction, followed by a summary of well-known disease-causing genes in one table, and supplemented with one or two diseases as example for detailed description. Here we aimed to raise more attention on rare lipoprotein metabolism diseases, calling for more work from basic research and clinical trials.

Observation and mechanism study of bladder wound healing after transurethral holmium laser resection of bladder tumor.

This research aims to observe and compare the wound healing process of urethral bladder after transurethral holmium laser resection of bladder tumor (HoLRBT) and transurethral resection of bladder tumor (TURBT) and explore the possible mechanism of wound healing and bladder re-epithelialization after HoLRBT. An animal model of canine achieving HoLRBT and TURBT was established. Cystoscopy was performed at different time points (3 days and 1, 2, 3, and 4 weeks) after operation to observe the wound healing and re-epithelialization of bladder epithelium. Bladder mucosa specimens were obtained and histopathological changes of the bladder epithelium were observed under light microscope after HE staining. Immunochemistry was used to determine the cell expression ofCK5, CK14, EGF, EGFR; microRNA expressions of CK5, CK14, EGF, and EGFR were measured by qRT-PCR. The changes of urinary EGF concentration were detected by ELISA. The bladder epithelial wound was repaired and re-epithelialized at 1 week after HoLRBT. At the 4th week, the bladder wound was basically completed and re-epithelialized; repair of bladder epithelial wounds recapitulates the wounds with the proliferation and migration of residual epithelial cells under the wound and the bladder epithelium that proliferates alongside the wound surface to complete re-epithelialization. The process begins at 1 week after surgery and basically completes at 4 weeks after surgery. CK5 and CK14 positive cells were detected in the basal cells of the bladder epithelium after HoLRBT, and the expression of CK5 and CK14 mRNA in the basal cells of the bladder epithelium under hyperplasia was significantly higher than that of the normal bladder epithelial basal cells. Bladder epithelial wound repair of TURBT group was performed by the proliferative differentiation of the peri-bladder epithelium adjacent to the wound edge and crawled to the wound surface to complete the re-epithelialization process. The wound repair and re-epithelialization were significantly slower than HoLRBT group. The CK5 and CK14 positive cells can also be detected in the basal cells of marginal hyperplasia of basal margin, and the expression of CK5 and CK14 mRNA in the basal cells of the peri-bladder hyperplasia is obviously higher than that of the normal bladder epithelial basal cells. The expression of EGF in bladder regenerating epithelium gradually increased with time after HoLRBT. Bladder basal cells and bladder regenerating epithelium express high levels of EGFR after HoLRBT. The concentration of EGF in urine after HoLRBT and TURBT increased significantly after surgery, and peaked at 3 days after operation. The urinary EGF concentration in HoLRBT group was higher than that in TURBT group at 3 and 4 weeks after operation. The re-epithelialization process can be seen 1 week after the cystectomy with holmium laser cystectomy, and the epithelialization rate is faster than the traditional transection surgery. This is because the residual bladder epithelial stem cells and wound marginal epithelial cells are involved in the process of wound repair and re-epithelialization following HoLRBT. But only the marginal epithelial tissue participates in the re-epithelialization process after TURBT, so the repair rate of TURBT is slower. The repair of bladder epithelium after HoLRBT is related to the stimulation of tissue factor EGF. The regenerated bladder epithelium also participates in the wound repair process by means of autocrine of EGF.