👤 Michael J Jurczak

Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD Show less

The biochemical and anthropometric consequences of metabolic disorders exert an enormous effect on the functioning of people worldwide. The aim of this study is to assess relationships between biochemical and anthropometric parameters associated with metabolic syndrome, and the presence of the PPAR-γ rs1801282, the FTO rs9939609, and the MC4R rs17782313 polymorphisms in women aged 45-60. The study included 425 women, aged 45-59 years, from the general population of the West Pomeranian Province in north-west Poland. The research procedure involved a structured interview, anthropometric and blood pressure measurements, biochemical analysis of serum, and genetic analysis. The carriers of the A/A genotype of the FTO polymorphism had higher LDL levels than their counterparts with the T/T genotype (p = 0.01). The carriers of the T/T genotype of the MC4R polymorphism had lower non-HDL levels than those with the C/C and C/T genotypes (p = 0.019). Weight was related to the C/C and the C/G + G/G genotypes of the PPAR-γ gene polymorphism (p = 0.046). The model of inheritance for the MC4R polymorphism had a significant effect on TG (p = 0.039) and non-HDL (p = 0.05) levels. The genotypes analyzed in the study had only a slight direct effect on the biochemical and anthropometric abnormalities typical of metabolic disorders. Nonetheless, the risk alleles (A allele of the FTO rs9939609 and the C allele of the MC4R rs17782313) were found to be related to lipid metabolism disorders in 45-60-year-old women. Show less

ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60-70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho-sphory-lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle. Show less

Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-ϵ activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a ≈ 70% increase in hepatic triglyceride uptake and ≈ 50% reduction hepatic triglyceride secretion. These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance. Show less