High expression of a vascular stricture-related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long-term survival after tolvaptan administration for liver cirrhosis.

AIM: Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis. METHODS: We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival. RESULTS: Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%). CONCLUSION: Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.

Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes.

The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy.

Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex.

RATIONALE: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 µM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis. CONCLUSIONS: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice.

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

Serum vaspin levels are associated with physical activity or physical fitness in Japanese: a pilot study.

AIM: To investigate the link between serum vaspin levels and physical activity and/or physical fitness in Japanese. METHODS: A total of 156 subjects (81 men and 75 women) was enrolled in this cross-sectional study. Serum vaspin levels, physical activity by uniaxial accelerometers, peak oxygen uptake, and metabolic risk parameters were evaluated. We also assessed anthropometric and body composition parameters. RESULTS: Serum vaspin levels were over the level of 10 ng/mL in 15 subjects (9.6 %: Vaspin High group). In Vaspin Low group (<5 ng/mL: 74 men and 67 women), serum vaspin levels were 0.12 ± 0.18 ng/mL in men and 0.39 ± 0.70 ng/mL in women. Peak oxygen uptake was significantly and positively correlated with serum vaspin levels even after adjusting for age, physical activity evaluated by Σ[metabolic equivalents × h per week (METs[Symbol: see text]h/w)], BMI, and other confounding factors in men. In turn, physical activity was significantly and positively correlated with serum vaspin levels even after adjusting for confounding factors in women. CONCLUSION: Serum vaspin levels were closely associated with physical fitness in men and physical activity in women independent of body composition in this Japanese cohort.

GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitor on Proximal Tubular Cells in DKD.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-ß1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-ß1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-ß1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-ß1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3).

INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.

Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice.

UNLABELLED: Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-α, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-α expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. CONCLUSION: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis.

RXR antagonism induces G0 /G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes.

The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease.

BACKGROUND: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (TH1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1). METHODS: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n=182). RESULTS: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 ± 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r=0.227, p=0.002), creatinine (r=0.175, p=0.018), urea nitrogen (r=0.162, p=0.028) and osmotic pressure (r=0.187, p=0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r=-0.188, p=0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p=0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3. CONCLUSION: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

Cell cycle abnormality in metabolic syndrome and nuclear receptors as an emerging therapeutic target.

In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.

Telmisartan attenuates diabetic nephropathy by suppressing oxidative stress in db/db mice.

BACKGROUND/AIMS: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. METHODS: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. RESULTS: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-ß) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. CONCLUSIONS: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress.

The serum vaspin levels are reduced in Japanese chronic hemodialysis patients.

BACKGROUND: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients. METHODS: Healthy Japanese control volunteers (control; n = 95, 49.9 ± 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 ± 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system. RESULTS: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin High group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin Low group). By comparing the patients in the Vaspin Low group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 ± 0.24 ng/ml) than in the HD patients (0.32 ± 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects. CONCLUSIONS: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin Low group.

Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study.

BACKGROUND: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown. OBJECTIVE: We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM. METHODS: A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays. RESULTS: Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.3-1234.6], p < 0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could predict the presence of diabetic microvascular complications. CONCLUSIONS: Elevated GPIHBP1 levels are associated with microvascular complications in T2DM and may help to predict their progression.

A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease.

Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin-/- obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2.

The adipose tissue is regarded as an endocrine organ and secretes bioactive adipokines modulating chronic inflammation and oxidative stress in obesity. Gal-9 is secreted out upon cell injuries, interacts with T-cell immunoglobulin-3 (Tim-3) and induces apoptosis in activated Th1 cells. Gal-9 also binds to protein disulfide isomerase (PDI), maintains PDI on surface of T cells, and increases free thiols in the disulfide/thiol cycles. To explore the molecular mechanism of obesity, we investigated Gal-9-/- and Gal-9wt/wt C57BL/6J mice fed with high fat-high sucrose (HFHS) chow. Gal-9-/- mice were resistant to diet-induced obesity associated with reduction of epididymal and mesenteric fat tissues and improved glucose tolerance compared with Gal-9wt/wt mice. However, the number of M1, M2 macrophages, and M1/M2 ratio in epididymal fat were unaltered. Under HFHS chow, Gal-9-/- mice receiving Gal-9-/- or Gal-9wt/wt bone marrow-derived cells (BMCs) demonstrated significantly lower body weight compared with Gal-9wt/wt mice receiving Gal-9-/- BMCs. We identified the binding between Gal-9 and peroxiredoxin-2 (PRDX2) in sugar chain-independent manner by nanoLC-MS/MS, immunoprecipitation, and pull-down assay. In 3T3L1 adipocytes, Gal-9 knockdown shifts PRDX2 monomer (reduced form) dominant from PRDX2 dimer (oxidized form) under oxidative stress with H2O2. The inhibition of Gal-9 in adipocytes may be a new therapeutic approach targeting the oxidative stress and subsequent glucose intolerance in obesity.

Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4.

MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir221 and Mir222 are paralogous genes and share the common seed sequence and Mir221/222AdipoKO mice fed with HFHS chow demonstrated resistance to the development of obesity compared with Mir221/222flox/y . Ddit4 is a direct target of Mir221 and Mir222, and the upregulation of Ddit4 in Mir221/222AdipoKO was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy.

Current Status of Familial LCAT Deficiency in Japan.

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

Corrigendum: Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control.

[This corrects the article DOI: 10.3389/fendo.2021.727915.].