Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2-related factor 2 nuclear translocation.

Activation of endoplasmic reticulum (ER) stress is involved in the development of nonalcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) has been reported to reduce hepatic steatosis, but the underlying mechanism has not been fully elucidated. Here, we investigated whether exendin-4 (EX-4), a GLP-1 receptor analogue, improves hepatic steatosis through ER stress reduction. Furthermore, we explored which ER stress pathway is involved in this process, with a focus on the protein kinase RNA-like ER kinase (PERK)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway. EX-4 treatment reduced hepatic lipid accumulation by suppressing the expression of lipogenic genes and restoring the expression of ß-oxidation genes in palmitate-treated HepG2 cells and high fat diet (HFD)-fed mice. In addition, EX-4 treatment suppressed hepatic ER stress activation in HFD-fed mice and tunicamycin-treated mice. In particular, EX-4 treatment restored HFD- and tunicamycin-induced Nrf2 nuclear translocation to control levels. Inhibition of Nrf2 by siRNA enhanced phosphorylation of PERK and eukaryotic translation initiation factor 2α (eIF2α), as well as other substrates of the PERK pathway. Nrf2 knockdown also inhibited the protective effects of EX-4 against lipid accumulation, ER stress activation, and cell death in palmitate-treated HepG2 cells. EX-4 treatment prevents hepatic steatosis and improves cell survival by regulating hepatic lipid metabolism and reducing ER stress activation, and Nrf2 plays an essential role in the protective effect of GLP-1 on hepatic steatosis.

Structural insight into molecular mechanism of poly(ethylene terephthalate) degradation.

Plastics, including poly(ethylene terephthalate) (PET), possess many desirable characteristics and thus are widely used in daily life. However, non-biodegradability, once thought to be an advantage offered by plastics, is causing major environmental problem. Recently, a PET-degrading bacterium, Ideonella sakaiensis, was identified and suggested for possible use in degradation and/or recycling of PET. However, the molecular mechanism of PET degradation is not known. Here we report the crystal structure of I. sakaiensis PETase (IsPETase) at 1.5 Å resolution. IsPETase has a Ser-His-Asp catalytic triad at its active site and contains an optimal substrate binding site to accommodate four monohydroxyethyl terephthalate (MHET) moieties of PET. Based on structural and site-directed mutagenesis experiments, the detailed process of PET degradation into MHET, terephthalic acid, and ethylene glycol is suggested. Moreover, other PETase candidates potentially having high PET-degrading activities are suggested based on phylogenetic tree analysis of 69 PETase-like proteins.

Differential association between sarcopenia and metabolic phenotype in Korean young and older adults with and without obesity.

OBJECTIVE: To determine whether sarcopenia was associated with metabolic phenotype in subjects with and without obesity. METHODS: A total of 6,021 participants (2,592 men, 3,429 women) aged 30 to 93 years were assessed using data from the 2009 Korea National Health and Nutrition Examination Survey. Sarcopenia was defined as appendicular skeletal muscle mass divided by weight (%) that is <1 SD below the sex-specific mean for young adults. Metabolically unhealthy was defined as ≥2 components of metabolic syndrome or the presence of hypertension, diabetes, or cardiovascular disease. Obesity was defined as body mass index ≥25.0 kg/m2 . RESULTS: Sarcopenia was associated with a metabolically unhealthy phenotype in nonobese men independent of age, smoking, regular physical activity, daily energy intake, total body fat, fasting insulin, non-HDL cholesterol, white blood cell count, ferritin level, and 25(OH) vitamin D level (OR per 1 SD increment (95% CI) 1.88 (1.28-2.75), P < 0.01), but this association was confounded by and not independent of total body fat in nonobese women. Sarcopenia was not associated with a metabolically unhealthy phenotype in subjects with obesity. CONCLUSIONS: Sarcopenia was independently associated with a metabolically unhealthy phenotype in nonobese men, but this association was not evident in nonobese women or subjects with obesity.

Association between the circulating total osteocalcin level and the development of cardiovascular disease in middle-aged men: a mean 8.7-year longitudinal follow-up study.

AIM: Recent studies have suggested that the serum osteocalcin level is associated with various cardiovascular risk factors. The aim of this study was to determine whether the serum total osteocalcin level is associated with the development of cardiovascular disease (CVD). METHODS: A total of 1,290 men 40-78 years of age were enrolled. The subjects were followed regularly at the Health Promotion Center on an outpatient basis and during hospitalization for a mean of 8.7 years, and the incidence of CVD (coronary heart disease [CHD] and stroke) was determined. RESULTS: At baseline, the body mass index, body fat percentage, fasting glucose, homeostasis model assessment-insulin resistance, triglyceride and non-high density lipoprotein (HDL) cholesterol levels were inversely and the HDL cholesterol levels were positively associated with the serum osteocalcin levels. In addition, the prevalence of diabetes or metabolic syndrome decreased as the osteocalcin tertile increased. However, no differences were observed in the prevalence of hypertension across the osteocalcin tertiles. Incident CVD occurred in 74 (5.7%) of the study subjects (29 patients with CHD and 47 patients with stroke). According to the Cox proportional hazards models, however, there were no statistical differences in the development of stroke, CHD or CVD across the osteocalcin tertiles after adjusting for other risk factors for CVD, including age, body mass index, current smoking, low-density lipoprotein cholesterol, diabetes, hypertension and the serum creatinine level. CONCLUSION: In conclusion, the serum total osteocalcin level was not associated with the development of CVD after adjusting for other risk factors for CVD in this cohort.