The effect of hyperthyroidism on cognitive function, neuroinflammation, and necroptosis in APP/PS1 mice.

BACKGROUND: Increasing evidence has linked the thyroid dysfunction to the pathogenesis of dementia. Evidence from clinical studies has demonstrated that hypothyroidism is related to an increased risk of dementia. But the association of hyperthyroidism with dementia is largely unknown. METHODS: We used the adenovirus containing thyrotropin receptor (TSHR) amino acid residues 1-289 (Ad-TSHR289)-induced Graves' disease (GD) phenotype in Alzheimer's disease (AD) model mice (APP/PS1 mice) to evaluate the effect of hyperthyroidism on the cognitive function and ß-amyloid (Aß) accumulation. RESULTS: GD mice exhibited a stable long-term hyperthyroidism and cognitive deficits. Single Cell RNA-sequencing analysis indicated that microglia function played a critical role in the pathophysiological processes in GD mice. Neuroinflammation and polarization of microglia (M1/M2 phenotype) and activated receptor-interacting serine/threonine protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudo-kinase (MLKL)-mediated necroptosis contributed to the pathological process, including Aß deposition and neuronal loss. RIPK3 inhibitor could inhibit GD-mediated Aß accumulation and neuronal loss. CONCLUSIONS: Our findings reveal that GD hyperthyroidism aggravates cognitive deficits in AD mice and induces Aß deposition and neuronal loss by inducing neuroinflammation and RIPK3/MLKL-mediated necroptosis.

Gut dysbiosis is associated with primary hypothyroidism with interaction on gut-thyroid axis.

Background Previous studies have shown that the gut microbiome is associated with thyroid diseases, including Graves' disease, Hashimoto's disease, thyroid nodules, and thyroid cancer. However, the association between intestinal flora and primary hypothyroidism remains elusive. We aimed to characterize gut microbiome in primary hypothyroidism patients. Methods Fifty-two primary hypothyroidism patients and 40 healthy controls were recruited. The differences in gut microbiota between the two groups were analyzed by 16S rRNA sequencing technology. Fecal microbiota transplantation (FMT) was performed in mice using flora from both groups; changes in thyroid function were then assessed in the mice. Results There were significant differences in α and ß diversities of gut microbiota between primary hypothyroidism patients and healthy individuals. The random forest analysis indicated that four intestinal bacteria (Veillonella, Paraprevotella, Neisseria, and Rheinheimera) could distinguish untreated primary hypothyroidism patients from healthy individuals with the highest accuracy; this was confirmed by receiver operator characteristic curve analysis. The short chain fatty acid producing ability of the primary hypothyroidism patients' gut was significantly decreased, which resulted in the increased serum lipopolysaccharide (LPS) levels. The FMT showed that mice receiving the transplant from primary hypothyroidism patients displayed decreased total thyroxine levels. Conclusions Our study suggests that primary hypothyroidism causes changes in gut microbiome. In turn, an altered flora can affect thyroid function in mice. These findings could help understand the development of primary hypothyroidism and might be further used to develop potential probiotics to facilitate the adjuvant treatment of this disease.

FSHR ablation induces depression-like behaviors.

Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr-/-). We found that Fshr-/- mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg-1 · d-1, i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr-/- mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.

Fenofibrate-induced hepatotoxicity: A case with a special feature that is different from those in the LiverTox database.

WHAT IS KNOWN AND OBJECTIVE: We report a special case of fenofibrate-induced acute severe DILI with sudden onset and rapid recovery, which is different from those in the LiverTox database. CASE SUMMARY DESCRIPTION: The acute severe DILI occurred within only 4 days after fenofibrate initial treatment for hypertriglyceridemia. Liver enzyme levels eventually declined to normal within two weeks after the discontinuation of fenofibrate. WHAT IS NEW AND CONCLUSION: Early detection of elevated hepatic enzymes after fenofibrate initial treatment helps physicians to avoid delayed diagnosis and subsequent treatment.

Exploring the link between obesity and hypothyroidism in autoimmune thyroid diseases: a metabolic perspective.

Background: The management of primary hypothyroidism demands a comprehensive approach that encompasses both the implications of autoimmune thyroid disease and the distinct effects posed by obesity and metabolic irregularities. Despite its clinical importance, the interplay between obesity and hypothyroidism, especially in the context of metabolic perspectives, is insufficiently explored in existing research. This study endeavors to classify hypothyroidism by considering the presence of autoimmune thyroid disease and to examine its correlation with various metabolic obesity phenotypes. Method: This research was conducted by analyzing data from 1,170 individuals enrolled in the Thyroid Disease Database of Shandong Provincial Hospital. We assessed four distinct metabolic health statuses among the participants: Metabolically Healthy No Obese Metabolically Healthy Obese Metabolically Unhealthy No Obese and Metabolically Unhealthy Obese Utilizing logistic regression, we investigated the association between various metabolic obesity phenotypes and hypothyroidism. Results: The study revealed a significant correlation between the Metabolically Unhealthy Obese (MUO) phenotype and hypothyroidism, particularly among women who do not have thyroid autoimmunity. Notably, the Metabolically Unhealthy No Obese (MUNO) phenotype showed a significant association with hypothyroidism in individuals with thyroid autoimmunity, with a pronounced prevalence in women. Furthermore, elevated levels of triglycerides and blood glucose were found to be significantly associated with hypothyroidism in men with thyroid autoimmunity and in women without thyroid autoimmunity. Conclusion: Effective treatment of hypothyroidism requires a thorough understanding of the process of thyroid autoimmune development. In patients without concurrent thyroid autoimmunity, there is a notable correlation between obesity and metabolic issues with reduced thyroid function. Conversely, for patients with thyroid autoimmunity, a focused approach on managing metabolic abnormalities, especially triglyceride levels, is crucial.

Expression of apelin­13 and its negative correlation with TGF­ß1 in patients with diabetic kidney disease.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes, one key feature of which includes renal fibrosis. As apelin is an adipokine closely related to diabetes, the present study aimed to evaluate apelin-13 expression levels and the relationship between apelin-13 and disease indicators in patients with diabetic kidney disease (DKD). The present case-control study enrolled 70 patients with diabetes, including 31 with diabetic kidney disease (DKD group), 39 without DKD (non-DKD group) and 30 healthy controls. The levels of serum apelin-13 and TGF-ß1, the key driver of renal fibrosis, were determined by ELISA. Additionally, age, mean disease duration, weight, blood pressure, fasting blood glucose, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein, cholesterol, urea nitrogen, blood creatinine and 24-hour urinary total protein (24-h UTP) were recorded. The results demonstrated that apelin-13 and TGF-ß1 expression levels, age, blood pressure, fasting blood glucose, cholesterol and blood urea nitrogen levels were significantly higher in patients with diabetes compared with the healthy controls (P<0.05). Moreover, apelin-13 and TGF-ß1 expression levels, mean disease duration, systolic pressure, blood creatinine, blood urea nitrogen and 24-h UTP were significantly higher in the DKD group compared with the non-DKD group (P<0.05). The estimated glomerular filtration rate (eGFR) was significantly reduced in the DKD group compared with the non-DKD group (P<0.05). Correlation analysis demonstrated a negative correlation between apelin-13 and eGFR expression and a positive correlation between apelin-13 expression and 24-h UTP in both the DKD and non-DKD groups (P<0.05). A negative correlation was also demonstrated between apelin-13 and TGF-ß1 expression levels in the DKD group and non-DKD groups (both P<0.05). In conclusion, apelin-13 and TGF-ß1 expression levels were significantly higher in the DKD group compared with those in the non-DKD group. Additionally, apelin-13 expression was negatively correlated with TGF-ß1 expression in the DKD and non-DKD groups. Therefore, apelin-13 could potentially be used in the future as an indicator of renal fibrosis or destruction in patients with DKD. The present trial was retrospectively registered in the Chinese Clinical Trial Registry (trial registration no. ChiCTR2200060945) on 14.06.2022.

The effect of G0S2 on insulin sensitivity: A proteomic analysis in a G0S2-overexpressed high-fat diet mouse model.

Background: Previous research has shown a tight relationship between the G0/G1 switch gene 2 (G0S2) and metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and obesity and diabetes, and insulin resistance has been shown as the major risk factor for both NAFLD and T2DM. However, the mechanisms underlying the relationship between G0S2 and insulin resistance remain incompletely understood. Our study aimed to confirm the effect of G0S2 on insulin resistance, and determine whether the insulin resistance in mice fed a high-fat diet (HFD) results from G0S2 elevation. Methods: In this study, we extracted livers from mice that consumed HFD and received tail vein injections of AD-G0S2/Ad-LacZ, and performed a proteomics analysis. Results: Proteomic analysis revealed that there was a total of 125 differentially expressed proteins (DEPs) (56 increased and 69 decreased proteins) among the identified 3583 proteins. Functional enrichment analysis revealed that four insulin signaling pathway-associated proteins were significantly upregulated and five insulin signaling pathway -associated proteins were significantly downregulated. Conclusion: These findings show that the DEPs, which were associated with insulin resistance, are generally consistent with enhanced insulin resistance in G0S2 overexpression mice. Collectively, this study demonstrates that G0S2 may be a potential target gene for the treatment of obesity, NAFLD, and diabetes.

Association of Obesity Based on Different Metabolic Status with Risk of Gout Occurrence in Patients: A National Study.

BACKGROUND: Obesity often co-exists with metabolic abnormalities, but the results of studies on the relationship between obesity, metabolic abnormalities and the risk of gout are inconsistent. OBJECTIVE: We aimed to study whether there was a mutual regulation between obesity, metabolic abnormalities and the risk of gout. METHOD: We conducted a cross-sectional study to expound the association between obesity based on different metabolic statuses and the risk of gout. Patients were derived from Nationwide Readmission Database (2018 sample). RESULTS: A total of 9,668,330 records were recruited for analysis from January to December. The risk of gout in the obesity group, metabolic abnormalities group and obesity combined with metabolic abnormalities group was 1.67 times (OR=1.67, 95%CI 1.64-1.70), 3.12 times (OR=3.12, 95%CI 3.09-3.15) and 4.27 times (OR=4.27, 95%CI 4.22-4.32) higher than that in the normal control group. For different metabolic components, OR value was highest in hypertension group (OR=2.65, 95%CI 2.60-2.70 and OR=4.85, 95%CI 4.73-4.97), followed by dyslipidemia group (OR=2.23, 95%CI 2.16-2.30 and OR=3.74, 95%CI 3.55-3.95) and in hyperglycemia group (OR=1.73, 95%CI 1.66-1.80 and OR=2.94, 95%CI 2.78-3.11). Fewer components of metabolic syndrome were associated with a lower risk of gout in both nonobese and obese patients. CONCLUSION: When metabolic abnormalities were present, obesity induced a higher risk of gout. Different components of metabolic abnormalities had different effects on the risk of gout occurrence, and the number of metabolic abnormalities was closely related to the risk of gout occurrence. Follow-up and intervention methods targeting obesity and metabolic abnormalities should be considered for patients with gout.

Association between Regional Body Muscle Mass and Non-Alcoholic Fatty Liver Disease: An Observational Study Using Data from the REACTION Study.

Background and aims: Regional muscle distribution is associated with abdominal obesity and metabolic syndrome. However, the relationship between muscle distribution and nonalcoholic fatty liver disease (NAFLD) remains unclear. This study was to determine the relationship between regional muscle distribution and the risk and severity of NAFLD. Methods: This cross-sectional study ultimately included 3161 participants. NAFLD diagnosed by ultrasonography was classified into three groups (non, mild, and moderate/severe). We estimated the regional body muscle mass (lower limbs, upper limbs, extremities, and trunk) through multifrequency bioelectrical impedance analysis (BIA). The relative muscle mass was defined as the muscle mass adjusted for the body mass index (BMI). Results: NAFLD participants accounted for 29.9% (945) of the study's population. Individuals with a higher lower limb, extremity, and trunk muscle mass had a lower risk of NAFLD (p < 0.001). Patients with moderate/severe NAFLD had a lower muscle mass of the lower limbs and trunk than patients with mild NAFLD (p < 0.001), while the muscle mass of the upper limbs and extremities did not differ significantly between the two groups. Moreover, similar results were found for both sexes and among different age groups. Conclusions: A higher muscle mass of the lower limbs, extremities, and trunk was negatively associated with the risk of NAFLD. A lower muscle mass of the limbs and trunk was inversely associated with the severity of NAFLD. This study provides a new theoretical basis for the development of individualized exercise prescriptions for the prevention of NAFLD in non-NAFLD patients.

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction.

Diabetes-associated cognitive decline (DCD), is one of the complications of diabetes, which is characterized by a series of neurophysiological and pathological abnormalities. However, the exact pathogenesis of DCD is still unknown. Single-cell RNA sequencing (scRNA-seq) could discover unusual subpopulations, explore functional heterogeneity and identify signaling pathways and potential markers. The aim of this research was to provide deeper opinion into molecular and cellular changes underlying DCD, identify different cellular types of the diabetic mice hippocampus at single-cell level, and elucidate the factors mediating the pathogenesis of DCD. To elucidate cell specific gene expression changes in the hippocampus of diabetic encephalopathy. Single-cell RNA sequencing of hippocampus from db/m and db/db mice was carried out. Subclustering analysis was performed to further describe microglial cell subpopulations. Interestingly using immunohistochemistry, these findings were confirmed at the protein level. Single cell analysis yielded transcriptome data for 14621 hippocampal cells and defined 11 different cell types. Analysis of differentially expressed genes in the microglia compartments indicated that infection- and immune system process- associated terms, oxidative stress and inflammation play vital roles in the progression of DCD. Compared with db/m mouse, experiments at the protein level supported the activation of microglia, increased expression of inflammatory factors and oxidative stress damage in the hippocampus of db/db mouse. In addition, a major finding of our research was the subpopulation of microglia that express genes related to pro-inflammatory disease-associated microglia (DAM). Our research reveals pathological alterations of inflammation and oxidative stress mediated hippocampal damage in the db/db mice, and may provide potential diagnostic biomarkers and therapeutic interventions for DCD.

Relationship between plasma 12,13-diHOME level and nonalcoholic fatty liver disease in patients with type 2 diabetes and obesity.

OBJECTIVE: 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) was one of the newly found lipokines. The goal of this study was to investigate whether the 12,13-diHOME was associated with related metabolic markers of nonalcoholic fatty liver disease (NAFLD) in a Chinese population with type 2 diabetes (T2DM) and obesity. METHODS: This cross-sectional study enrolled 202 subjects with T2DM. Anthropometric parameters, 12,13-diHOME, serum lipids levels, fasting blood-glucose (FBG), serum glycosylated hemoglobin (HbA1c), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), liver and kidney function parameters were collected. NAFLD was diagnosed based on abdominal ultrasonography examination results. A computer-aided ultrasound quantitative method was applied to evaluate the liver fat content (LFC). RESULTS: The number of the patients with fatty liver was 139 (68.81%) and those with non-fatty liver was 63 (31.19%). Subjects with NAFLD had a higher body mass index (BMI), diastolic blood pressure, serum alanine aminotransferase (ALT), triglyceride (TG), HOMA-IR, LFC, p＜0.05 for all. But no significant difference was found in plasma 12,13-diHOME level (p=0.967), though its level trend was higher in non-NAFLD group. Plasma 12,13-diHOME was positively correlated with aspartate aminotransferase (AST), total cholesterol (TC), high density lipoprotein cholesterol (HDLC), blood urea nitrogen (BUN), free fatty acid (FFA), C-peptide, FINS and HOMAIR. It was negatively correlated with height, body weight, glomerular filtration rate (eGFR) and HbA1c. CONCLUSIONS: Although 12,13-diHOME was correlated with AST, TC, HDL-C, BUN, FFA, C-peptide, FINS, HOMA-IR, eGFR and HbA1c, there was no significant difference in 12,13-diHOME level between the two groups. However, more research should be carried on about this newly found lipokine.

Statin Use and Benefits of Thyroid Function: A Retrospective Cohort Study.

Purpose: Previous studies have suggested that cholesterol may influence thyroid function. Since statins are widely used for their cholesterol-lowering effect, we aimed to assess the association between statin use and thyroid function, and also to explore the role of the cholesterol-lowering effect in it. Methods: We performed a retrospective cohort study derived from REACTION study. Eligible subjects receiving statin therapy were included in the statin group, and sex-, age-, total cholesterol (TC)-, and thyroid function-matched participants without lipid-lowering therapy were included in the control group. The median follow-up time was three years. Outcomes of thyroid function were evaluated at the end of follow-up. We used multivariable regression models to assess the association between statin use and outcomes of thyroid function, and also performed mediation analyses to explore the role of cholesterol in it. Results: A total of 5,146 participants were screened, and 201 eligible subjects in the statin group and 201 well-matched subjects in the control group were analyzed. At the end of follow-up, TC and thyroid-stimulating hormone (TSH) levels in the statin group were lower than those in the control group (both p < 0.05), and the percentage of euthyroid subjects was higher in the statin group (88.06% vs. 76.12%, p = 0.002). The incidence rate of subclinical hypothyroidism (SCH) in euthyroid subjects was lower in the statin group (6.29% vs. 14.86%, p = 0.009), and the remission rate among subjects with SCH was higher in the statin group (50.00% vs. 15.38%, p = 0.008). In multivariable regression analyses, statin use was independently associated with lower TSH levels and higher odds to be euthyroid (OR 2.335, p = 0.004) at the end of follow-up. Mediation analyses showed the association between statin use and TSH levels were mediated by TC changes during follow-up. Conclusion: Statin use was associated with benefits of thyroid function, and TC changes serve as a mediator of the association between statin use and TSH levels. Further studies are needed to clarify the possible underlying mechanism.

Prevalence of mild cognitive impairment in type 2 diabetes mellitus is associated with serum galectin-3 level.

AIMS/INTRODUCTION: Galectin-3 (Gal3) contributes to insulin resistance, inflammation and obesity, the three risk factors for mild cognitive impairment (MCI) in type 2 diabetes mellitus patients. MATERIALS AND METHODS: A total of 134 hospitalized type 2 diabetes mellitus patients were assessed by the Montreal Cognitive Assessment method, and divided into 65 MCI and 69 controls. Levels of variables, Gal3 and Aß42, were investigated in relation with cognitive function in both type 2 diabetes mellitus patients with MCI and high-fat diet/streptozotocin induced type 2 diabetes mellitus rats. RESULTS: Significantly higher levels of serum Gal3 and lower levels of plasma Aß42 (all P < 0.05) were found in the MCI type 2 diabetes mellitus group as compared with the non-MCI type 2 diabetes mellitus control. Partial correlation analysis showed that Gal3 is negatively correlated with both MMSE score (r = -0.51, P < 0.01) and Montreal Cognitive Assessment score (r = -0.47, P < 0.001) after adjustment for glycated hemoglobin, homoeostasis model assessment of insulin resistance and Aß42 in all type 2 diabetes mellitus patients, with a stronger effect seen in the MCI type 2 diabetes mellitus group after further analysis with MCI strata. A simple logistic regression model showed that Gal3 and Aß42 are significantly associated with MCI type 2 diabetes mellitus patients after adjustment with the covariates sex, age, body mass index, glycated hemoglobin, homoeostasis model assessment of insulin resistance and antidiabetic drugs. Serum and brain Gal3 levels were significantly increased in high-fat diet/streptozotocin diabetic rats, which correlate to the impairment of learning and memory ability. Gal3 inhibitor modified citrus pectin decreased serum and brain Gal3 levels in diabetic rats, accompanied by the amelioration of learning and memory impairment. CONCLUSIONS: Gal3 might be associated with cognitive impairment in type 2 diabetes mellitus, and serum Gal3 level might be a new risk factor of MCI in type 2 diabetes mellitus patients.

TSH promotes adiposity by inhibiting the browning of white fat.

Adiposity is caused by an imbalance between energy intake and consumption. Promotion of the browning of white fat increases energy expenditure and could combat adiposity. Thyroid-stimulating hormone (TSH) has been confirmed to positively correlate with adiposity. However, the putative connection between TSH and white adipose browning has never been explored. In this study, we sought to assess the effect of TSH on white adipose tissue browning and energy metabolism. Subclinical hypothyroidism mice, thyroid-specific Tshr-knockout mice injected with TSH, adipocyte-specific and global Tshr-knockout micewere subjected to morphological, physiological, genetic or protein expression analyses and metabolic cages to determine the role of TSH on the browning of white adipose tissue and metabolism. 3T3-L1 and primary SVF cells were used to verify the effects and mechanism of TSH on the browning of white adipocytes. We show that increased circulation TSH level decreases energy expenditure, promotes adiposity, impairs glucose and lipid metabolism. Knockout of Tshr decreases adiposity, increases energy expenditureand markedly promotes the development of beige adipocytesin both epididymal and inguinal subcutaneous white fat via a mechanism that likely involves AMPK/PRDM16/PGC1α. Our results reveal an important role of TSH in regulating energy balance and adiposity by inhibiting the browning of white fat.

Pharmacological Inhibition of Galectin-3 Ameliorates Diabetes-Associated Cognitive Impairment, Oxidative Stress and Neuroinflammation in vivo and in vitro.

BACKGROUND: In diabetes, cognitive impairment is linked with oxidative stress and neuroinflammation. As the only chimeric member of the galectin family, galectin-3 (Gal3) induces neuroinflammation and cognitive impairment in models of Alzheimer's disease (AD); however, its role in diabetes-associated cognitive impairment is not established. METHODOLOGY: Here, we investigated the effects of Gal3 inhibition on cognitive impairment and the possible underlying molecular events in diabetes. We investigated the effects of the Gal3 inhibitor modified citrus pectin (MCP; 100 mg/kg/day oral for 6 weeks) in vivo in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic rats. Additionally, the effects of MCP on high glucose (HG)-stimulated BV-2 microglial cells were investigated in vitro. RESULTS: We found that MCP attenuated memory impairment in diabetic rats in the Morris water maze test and reduced insulin resistance, oxidative stress, and neuroinflammation. In HG-stimulated BV-2 microglial cells, MCP increased cell viability and decreased oxidative stress and the production of proinflammatory cytokines. CONCLUSION: The results of this study indicate that the inhibition of Gal3 by MCP ameliorates diabetes-associated cognitive impairment, oxidative stress, and neuroinflammation, suggesting that Gal3 could be a potential new target for therapeutic intervention to prevent cognitive impairment in diabetes.

Therapeutic targets of hypercholesterolemia: HMGCR and LDLR.

Cholesterol homeostasis is critical and necessary for the body's functions. Hypercholesterolemia can lead to significant clinical problems, such as cardiovascular disease (CVD). 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and low-density lipoprotein cholesterol receptor (LDLR) are major points of control in cholesterol homeostasis. We summarize the regulatory mechanisms of HMGCR and LDLR, which may provide insight for new drug design and development.

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol.

Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHß antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/ß-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

SREBP-2, a new target of metformin?

BACKGROUND: Metformin, as the first-line treatment anti-diabetic drug, represents increasing evidence of a potential efficacy in improving dyslipidemia. However, the exact molecular mechanism(s) by which metformin influences lipid metabolism remains incompletely understood. METHODS: The HepG2 cells were treated with metformin and the AMP-activated protein kinase (AMPK) inhibitor compound C or a dominant-negative form of AMPK plasmid. ELISA assay was employed to measure AMPK activity, and cellular cholesterol content was determined by enzymatic colorimetric method. RT-PCR and western blotting were used to detect SREBP-2 mRNA levels and its target protein levels. RESULTS: We found that metformin significantly stimulated AMPK activity and decreased intracellular total cholesterol contents in HepG2 cells. Metformin reduced the sterol regulatory element-binding protein-2 (SREBP-2) and its downstream target proteins and increased low-density lipoprotein receptor (LDLR) levels. CONCLUSION: Our preliminary results demonstrate that metformin as a first-line and initial medication suppresses the synthesis of SREBP-2 and upregulates LDLR, and consequently decreases cholesterol production via activation of AMPK, at least partly. These findings suggest a therapeutic target and potential beneficial effects of metformin on the prevention of dyslipidemia or related diseases.

Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic and progressive liver disease with an increased risk of morbidity and mortality. However, so far no specific pharmacotherapy has been approved. Gynostemma pentaphylla (Thunb.) Makino (GP) is a traditional Chinese medicine that is widely used against hyperlipemia as well as hyperglycemia. This study aims to evaluate the effect of GP on NAFLD and explore the possible mechanism. METHODS: High-fat-diet induced NAFLD mice model were orally administrated with GP at dose of 11.7 g/kg or equivalent volume of distilled water once a day for 16 weeks. Body weight, food intake and energy expenditure were assessed to evaluate the general condition of mice. The triglycerides, total cholesterol content in the liver and liver histopathology, serum lipid profile and serum insulin level, fecal microbiome, hepatic microRNAs and relative target genes were analyzed. RESULTS: Mice in GP treatment group displayed improved hepatic triglycerides content with lower lipid droplet in hepatocyte and NAFLD activity score. Besides, GP treatment altered the composition of gut microbiota and the relative abundance of some of the key components that are implicated in metabolic disorders, especially phylum Firmicutes (Eubacterium, Blautia, Clostridium and Lactobacillus). Several hepatic microRNAs were downregulated by GP treatment such as miR-130a, miR-34a, miR-29a, miR-199a, among which the expression miR-34a was altered by more than four-fold compared to that of HFD group (3:14). The correlation analysis showed that miR-34a was strongly related to the change of gut microbiota especially phylum Firmicutes (R = 0.796). Additionally, the target genes of miR-34a (HNF4α, PPARα and PPARα) were restored by GP both in mRNA and protein levels. CONCLUSION: Our results suggested that GP modulated the gut microbiota and suppressed hepatic miR-34a, which was associated with the amelioration of hepatic steatosis.

Role of exosome-associated microRNA in diagnostic and therapeutic applications to metabolic disorders.

Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative stress, which may change cellular functions, are considered to play an essential role in the pathogenetic progress of metabolic disorders. Recent studies have found that cells secrete nanoscale vesicles containing proteins, lipids, nucleic acids, and membrane receptors, which mediate signal transduction and material transport to neighboring and distant cells. Exosomes, one type of such vesicles, are reported to participate in multiple pathological processes including tumor metastasis, atherosclerosis, chronic inflammation, and insulin resistance. Research on exosomes has focused mainly on the proteins they contain, but recently the function of exosome-associated microRNA has drawn a lot of attention. Exosome-associated microRNAs regulate the physiological function and pathological processes of metabolic disorders. They may also be useful as novel diagnostics and therapeutics given their special features of non-immunogenicity and quick extraction. In this paper, we summarize the structure, content, and functions of exosomes and the potential diagnostic and therapeutic applications of exosome-associated microRNAs in the treatment of metabolic disorders.