The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.

BACKGROUND: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms. METHODS: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective ß-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction. RESULTS: Treadmill exercise markedly induced cardiac expression of ß-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of ß-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM. CONCLUSIONS: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03240978.

Hepatic PRMT1 ameliorates diet-induced hepatic steatosis via induction of PGC1α.

Rationale: Over-nutrition will lead to overexpression of PRMT1 but protein hypomethylation is observed in the liver of obese subjects. The dynamic alteration of the expression and methyltransferase activity of PRMT1 in the progression of fatty liver diseases remains elusive. Methods: We used recombinant adeno-associated virus-mediated gene delivery system to manipulate the hepatic PRMT1 expression level in diet-induced obese mice to investigate the role of PRMT1 in hepatic steatosis. We further utilized a cohort of obese humans with biopsy-proven nonalcoholic fatty liver disease to support our observations in mouse model. Results: We demonstrated that knockdown of PRMT1 promoted steatosis development in liver of high-fat diet (HFD) fed mice. Over-expression of wild-type PRMT1, but not methyltransferase-defective mutant PRMT1G80R, could alleviate diet-induced hepatic steatosis. The observation is conserved in the specimens of obese humans with biopsy-proven nonalcoholic fatty liver disease. Mechanistically, methyltransferase activity of PRMT1 was required to induce PGC-1α mRNA expression via recruitment of HNF-4α to the promoter of PGC-1α, and hence attenuated HFD-induced hepatic steatosis by enhancing PGC-1α-mediated fatty acid oxidation. Conclusions: Our results identify that activation of the PRMT1/HNF-4α/PGC-1α signaling is a potential therapeutic strategy for combating non-alcoholic fatty liver disease of obese subjects.

A Fast Decline of Residual Renal Function in the First Year is a Predictor for Early Withdrawal from Peritoneal Dialysis in Non-Diabetic Patients.

BACKGROUND/AIMS: Little is known about the relationship between residual renal function (RRF) decline in early period and survival in non-diabetic peritoneal dialysis (PD) patients. METHODS: A total of 567 non-diabetic patients who began PD from January 1, 2005 to June 30, 2013 was investigated. The rate of RRF decline was determined by the "slope of the trend equation" of serial RRFs. A composite end-point of all-cause mortality and conversion to hemodialysis (HD) was used, survival status was censored on June 30, 2016. RESULTS: The median of "the slope of RRF decline equation" was 0.308 (0.001-2.111) ml/min/1.73 m2/ month. In the median follow-up period of 43 months (range 12 to 120 months), 65 (11.5%) patients died, 90 (15.9%) patients converted to HD and 171 (30.2%) patients received kidney transplantation. Multivariate linear regression showed male, high baseline RRF, high baseline peritoneal Kt/V urea, low serum albumin and low uric acid were independently associated with the rate of RRF decline in the first year of PD. Multivariate Cox models revealed that RRF decline in the first year remained a predictor for composite end-point (HR, 2.74, 95% CI, 1.53 to 4.90, P=0.001). The patients were divided into high RRF decline group (> 0.308ml/ min/1.73m2/month) and low RRF decline group (≤0.308 ml/min/1.73m2/month). In the first three years of PD, the rate of end-point events was higher in high RRF decline group (23.2%) than that in low RRF decline group (11.0%) (P< 0.001). There were 189 patients in low RRF decline group and 171 patients in high RRF decline group maintaining PD for more than 3 years, in a median follow-up of 54 months (range 37 to 120 months), the survival rate was 30.9% in high RRF decline group and 46.4% in low RRF decline group (P=0.883). In high RRF decline group, there were 92 patients reaching composited end-point and 112 patients maintaining PD; multivariate Cox model showed high peritoneal Kt/V urea after 1 year of PD and high albumin level were protective factors (HR, 0.29, 95% CI, 0.13 to 0.61, P= 0.001; HR, 0.94, 95% CI, 0.90-0.99, P=0.022, respectively), while fast RRF decline remained risk factor for composite end-point (HR, 3.28, 95% CI,1.48-7.31, P=0.004). CONCLUSION: A faster RRF decline in the first year was a predictor for all-cause mortality and conversion to HD in non-diabetic PD patients, mainly in the first three year. For patients with faster RRF decline, increasing PD dose was effective to improve survival.

Association Between Comprehensive Nutritional Scoring System (CNSS) and Outcomes of Continuous Ambulatory Peritoneal Dialysis Patients.

BACKGROUND/AIMS: The presence of protein-energy wasting (PEW) among dialysis patients is a crucial risk factor for outcomes. The complicated pathogenesis of PEW makes it difficult to assess and treat. This single-center retrospective study focuses on the association between nutritional markers and the outcomes of continuous ambulatory peritoneal dialysis(CAPD) patients, aiming to establish a practical comprehensive nutritional scoring system for CAPD patients. METHODS: 924 patients who initiated peritoneal dialysis in our center from January 1st,2005 to December 31st,2015 were enrolled. Comprehensive nutritional scoring system(CNSS) was based on items including SGA, BMI, ALB, TC, MAC and TSF. We divide patients into 3 groups according to their CNSS score. Outcomes including mortality, hospitalization days and hospitalization frequency were compared between 3 grades. RESULTS: The CNSS grade correlated significantly with hospitalization days (P<0.05). Both categorized CNSS grade (HR:0.56; 95% CI:0.41-0.78; P = 0.001) and continuous CNSS score (HR:0.87; 95% CI: 0.80-0.94; P = 0.001) independently protect PD patients from all-cause mortality. CONCLUSION: CNSS provides an integrated scoring system with significant associations with hospitalization and mortality in PD patients. The CNSS grade differentiates patients with malnutritional risk and independently predicts high risk of morbidity and mortality.

Association of very Low-density Lipoprotein Cholesterol with All-cause and Cardiovascular Mortality in Peritoneal Dialysis.

BACKGROUND/AIMS: Cardiovascular disease (CVD) is the leading cause of death in dialysis patients. Little is known about the relationship between very low-density lipoprotein cholesterol (VLDL-C) and cardiovascular mortality in these patients. METHODS: A total of 1324 incident patients who began continuous ambulatory peritoneal dialysis (CAPD) therapy at our hospital between January 1, 2005, and September 30, 2014, with baseline serum VLDL-C values were investigated. The associations of the VLDL-C levels with all-cause and cardiovascular mortality were assessed. RESULTS: The mean age of the cohort was 50.2 ± 14.8 years, and the mean VLDL-C level was 33.6 ± 18.0 mg/dl. One hundred sixty-five (12.5%) patients died during the study period. Multivariable models revealed that the high VLDL-C group was associated with significantly higher all-cause (HR, 2.08, 95% CI, 1.13 to 3.29, P = 0.002) and cardiovascular mortality (HR, 1.92, 95% CI, 1.18 to 4.29, P = 0.013) compared with the low VLDL-C group even after adjusting for various covariates. Using the VLDL-C level as a continuous variable, the hazard ratios (HRs) of all-cause and cardiovascular mortality associated with a 10-mg/dl increase in VLDL-C level were 1.12 (95% CI, 1.02 to 1.26, P = 0.025) and 1.11 (95% CI, 1.02 to 1.22, P = 0.029), respectively. VLDL-C was associated more strongly to all-cause (e.g., Akaike information criteria of 1990.205 vs. 1994.451) and cardiovascular (e.g., Akaike information criteria of 984.146 vs. 985.634) mortality than triglyceride (TG) levels. CONCLUSIONS: An elevated VLDL-C level is an independent risk factor for all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients.

Peritoneal dialysis for autosomal dominant polycystic kidney disease: a retrospective study.

To describe the long-term clinical outcomes of patients with autosomal dominant polycystic kidney disease (ADPKD) who are on peritoneal dialysis (PD) therapy. We performed a retrospective matched-cohort analysis comparing the clinical outcomes of 30 ADPKD patients with those of 30 non-diabetic patients who had bilateral small kidneys between July 1 2007 and July 31 2014. The patient groups were matched by age, gender, and time of PD initiation. There were no significant differences in the demographic or biochemical parameters, comorbid conditions, residual glomerular filtration rate, or Charlson comorbidity score at the beginning of PD. The median renal volume was 1315 ml for the ADPKD group and 213 ml for the control group. Patients with ADPKD had similar 3-year patient survival (90.6% versus 86.3%, P=0.807) and technique survival (89.2% versus 74.3%, P=0.506) compared with non-ADPKD patients. Also, there was no significant difference in the peritonitis-free survival between the ADPKD and control groups (P=0.22), and rates of peritonitis were similar (0.19 versus 0.21 episodes per patient-year, P=0.26). No differences were observed in the incidence of PD-related complications, such as hernia and dialysate leak. ADPKD is not a contraindication for PD, and a subgroup of ADPKD patients with relatively small kidney volume can be treated using PD.