Recently, the beneficial effects of increased physical activity (PA) on nonalcoholic fatty liver disease (NAFLD) in obese subjects were reported. However, the optimal strength and volume of PA in ...lifestyle modification to improve NAFLD pathophysiology and be recommended as an appropriate management of this condition are unclear. The primary goal of this retrospective study was to estimate the beneficial effects of a varying volume of moderate to vigorous intensity PA (MVPA) on the improvement of NAFLD. A total of 169 obese, middle‐aged men were enrolled in a 12‐week weight reduction program through lifestyle modification consisting of dietary restrictions plus aerobic exercise. Among these obese subjects, 40 performed MVPA for <150 min·wk−1, 42 performed MVPA for 150‐250 min·wk−1, and 87 performed MVPA for >250 min·wk−1. The subjects in the MVPA ≥250 min·wk−1 group, in comparison with those in the MVPA <250 min·wk−1 group, showed significantly attenuated levels of hepatic steatosis (−31.8% versus −23.2%). This attenuation was likely independent of the detectable weight reduction. MVPA for ≥250 min·wk−1 in comparison with that for <150 min·wk−1 led to a significant decrease in the abdominal visceral adipose tissue severity (−40.6% versus −12.9%), levels of ferritin (−13.6% versus +1.5%), and lipid peroxidation (−15.1% versus −2.8%), and a significant increase in the adiponectin levels (+17.1% versus +5.6%). In association with these changes, the gene expression levels of sterol regulatory element‐binding protein‐1c and carnitine palmitoyltransferase‐1 in peripheral blood mononuclear cells also significantly decreased and increased, respectively. Conclusion: MVPA for ≥250 min·wk−1 as part of lifestyle management improves NAFLD pathophysiology in obese men. The benefits seem to be acquired through reducing inflammation and oxidative stress levels and altering fatty acid metabolism. (Hepatology 2015;61:1205–1215)
Cockayne syndrome (CS) is a recessive disorder that results in deficiencies in transcription-coupled nucleotide excision repair (TC-NER), a subpathway of nucleotide excision repair, and cells from CS ...patients exhibit hypersensitivity to UV light. CS group B protein (CSB), which is the gene product of one of the genes responsible for CS, belongs to the SWI2/SNF2 DNA-dependent ATPase family and has an ATPase domain and an ubiquitin-binding domain (UBD) in the central region and the C-terminal region, respectively. The C-terminal region containing the UBD is essential for the functions of CSB. In this study, we generated several CSB deletion mutants and analyzed the functions of the C-terminal region of CSB in TC-NER. Not only the UBD but also the C-terminal 30-amino acid residues were required for UV light resistance and TC-NER. This region was needed for the interaction of CSB with RNA polymerase II, the translocation of CS group A protein to the nuclear matrix, and the association of CSB with chromatin after UV irradiation. CSB was modified by small ubiquitin-like modifier 2/3 in a UV light-dependent manner. This modification was abolished in a CSB mutant lacking the C-terminal 30 amino acid residues. However, the substitution of lysine residues in this region with arginine did not affect SUMOylation or TC-NER. By contrast, substitution of a lysine residue in the N-terminal region with arginine decreased SUMOylation and resulted in cells with defects in TC-NER. These results indicate that both the most C-terminal region and SUMOylation are important for the functions of CSB in TC-NER.
Transcription‐coupled nucleotide excision repair (TC‐NER) is a subpathway of nucleotide excision repair that efficiently removes transcription‐blocking DNA damage from the transcribed strands of ...active genes. UVSSA is a causative gene for UV‐sensitive syndrome (UVSS), which is an autosomal recessive disorder characterized by hypersensitivity to UV light and deficiency in TC‐NER. UV‐stimulated scaffold protein A (UVSSA), the product of UVSSA, forms a complex with ubiquitin‐specific peptidase 7 (USP7) and is stabilized by interaction with USP7. The central region of UVSSA, which contains the tumor necrosis factor receptor‐associated factor (TRAF)‐binding motif, is required for the interaction with the N‐terminal TRAF domain of USP7. Here, we showed that UVSSA is mono‐ubiquitinated in vitro and identified a lysine residue (Lys414) in UVSSA as the target of ubiquitination. The deubiquitination activity of USP7 was inhibited by the ubiquitin‐conjugating enzyme UbcH6. Lys414 was also modified by poly‐ubiquitin chains in vivo. UVSSA deficient in the interaction with USP7 is ubiquitinated and degraded by the proteasome, and the degradation leads to deficiency in TC‐NER. The substitution of Lys414 by Arg of UVSSA inhibited its degradation and thereby suppressed the deficiency in TC‐NER.
UVSSA is a specific factor for transcription‐coupled nucleotide excision repair (TC‐NER) and interacts with USP7. We identified K414 in UVSSA as a ubiquitination target site. UVSSAS254A is deficient in the interaction with USP7 and rapidly degraded by proteasome, and the degradation leads to deficiency in TC‐NER. The substitution of K414R inhibited its degradation and thereby suppressed the deficiency in TC‐NER.
Weight reduction remains the most common therapy advocated for the treatment of obesity-related liver diseases. Recently, a beneficial effect of exercise regimens for liver dysfunction, independent ...of weight reduction, has been reported. Therefore, a retrospective analysis was conducted to determine whether exercise training without dietary restriction in obese, middle-age men influences the pathophysiology of abnormal liver function.
A total of 108 subjects who completed a 12-wk exercise training program without any dietary restriction were analyzed in this study; these results were compared with those of 104 subjects who completed a 12-wk dietary restriction program. Furthermore, 42 of these subjects (from both groups) who had abnormal liver function and suspicious liver fibrosis by nonalcoholic fatty liver disease fibrosis score were analyzed to obtain a more concrete outcome for exercise-training effects.
In exercise training, although the magnitude of body-weight reduction (-3.1% vs -8.5%), waist circumference (-4.0% vs -7.1%), and visceral adipose tissue area (-12.2% vs -22.5%) was significantly more modest than that achieved by dietary restriction, exercise training elicited equivalent reductions in serum alanine aminotransferase and gamma glutamyl transpeptidase levels (-20.6% vs -16.1% and -25.7% vs -34.0%) and equivalent improvement of insulin resistance (-29.7% vs -26.9%). Moreover, exercise training remarkably increased the serum adiponectin level (+33.4% vs +15.1%). Importantly, for subjects with abnormal liver function and suspicious liver fibrosis, exercise training was effective in reducing the serum levels of inflammation and oxidative stress markers: ferritin and thiobarbituric acid reactive substances (-25.0% vs +1.1% and -33.5% vs -10.5%).
Exercise training benefits the management of obesity-related liver diseases independent of detectable weight reduction. Particularly, these effects seem to be acquired through an improvement in the hepatic inflammatory condition and its related oxidative stress levels.
Obesity has reached global epidemic proportions and is associated with multiple comorbidities, including cardiovascular disease. A novel predictor of cardiovascular disease is elevated central ...systolic blood pressure. In fact, lifestyle modifications have been shown to decrease the central systolic blood pressure in overweight and obese men. The mechanism underlying these changes has yet to be fully elucidated. Interestingly, testosterone has been found to have cardioprotective effects. Moreover, serum testosterone levels are lower in obese men than in normal weight men. However, it is still unclear whether testosterone participates in the decrease of central blood pressure in overweight and obese men following lifestyle modifications. So, the purpose of the present study was to investigate the effect of testosterone on central systolic blood pressure in overweight and obese men before and after the 12-week lifestyle modification program. Forty-four overweight and obese men completed a 12-week lifestyle modification program (aerobic exercise training and dietary modifications). For all participants, central systolic blood pressure and serum testosterone levels were measured before and after the program. After the program, central systolic blood pressure was significantly decreased while serum total testosterone levels were significantly increased in overweight and obese men. Moreover, we also found a significant negative relationship between the change in serum testosterone levels and that in central systolic blood pressure. The present study suggests that increased serum testosterone levels likely contribute to a decrease in central blood pressure in overweight and obese men.
The emerging link between iron metabolism and genome integrity is increasingly clear. Recent studies have revealed that MMS19 and cytosolic iron-sulfur cluster assembly (CIA) factors form a complex ...and have central roles in CIA pathway. However, the composition of the CIA complex, particularly the involvement of the Fe-S protein IOP1, is still unclear. The roles of each component are also largely unknown. Here, we show that MMS19, MIP18, and CIAO1 form a tight “core” complex and that IOP1 is an “external” component of this complex. Although IOP1 and the core complex form a complex both in vivo and in vitro, IOP1 behaves differently in vivo. A deficiency in any core component leads to down-regulation of all of the components. In contrast, IOP1 knockdown does not affect the level of any core component. In MMS19-overproducing cells, other core components are also up-regulated, but the protein level of IOP1 remains unchanged. IOP1 behaves like a target protein in the CIA reaction, like other Fe-S helicases, and the core complex may participate in the maturation process of IOP1. Alternatively, the core complex may catch and hold IOP1 when it becomes mature to prevent its degradation. In any case, IOP1 functions in the MMS19-dependent CIA pathway. We also reveal that MMS19 interacts with target proteins. MIP18 has a role to bridge MMS19 and CIAO1. CIAO1 also binds IOP1. Based on our in vivo and in vitro data, new models of the CIA machinery are proposed.
Background: The CIA machinery in human cells is unclear.
Results: MMS19 formed a complex with MIP18, CIAO1, and IOP1, but IOP1 behaved differently from the other components.
Conclusion: The CIA complex consists of a core MMS19-MIP18-CIAO1 complex, and IOP1 is an external component of the CIA machinery.
Significance: This study increases the understanding of the composition of the CIA machinery in human cells and the interactions between the components.
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•Xpa−/− mice accumulate more cyclopurine lesions in the brain tissues than wt mice.•The findings support the hypothesis for the development of XP neurological disease.•The ELISA ...sensitivity was increased to quantify cyclopurine lesions in mouse tissues.
Xeroderma pigmentosum (XP) is a genetic disorder associated with defects in nucleotide excision repair, a pathway that eliminates a wide variety of helix-distorting DNA lesions, including ultraviolet-induced pyrimidine dimers. In addition to skin diseases in sun-exposed areas, approximately 25% of XP patients develop progressive neurological disease, which has been hypothesized to be associated with the accumulation of an oxidatively generated type of DNA damage called purine 8,5′-cyclo-2′-deoxynucleoside (cyclopurine). However, that hypothesis has not been verified. In this study, we tested that hypothesis by using the XP group A gene-knockout (Xpa−/−) mouse model. To quantify cyclopurine lesions in this model, we previously established an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody (CdA-1) that specifically recognizes 8,5′-cyclo-2′-deoxyadenosine (cyclo-dA). By optimizing conditions, we increased the ELISA sensitivity to a detection limit of ˜one cyclo-dA lesion/106 nucleosides. The improved ELISA revealed that cyclo-dA lesions accumulate with age in the brain tissues of Xpa−/− and of wild-type (wt) mice, but there were significantly more cyclo-dA lesions in Xpa−/− mice than in wt mice at 6, 24 and 29 months of age. These findings are consistent with the long-standing hypothesis that the age-dependent accumulation of endogenous cyclopurine lesions in the brain may be critical for XP neurological abnormalities.
The xeroderma pigmentosum group C (XPC) protein complex plays a key role in recognizing DNA damage throughout the genome for mammalian nucleotide excision repair (NER). Ultraviolet light (UV)-damaged ...DNA binding protein (UV-DDB) is another complex that appears to be involved in the recognition of NER-inducing damage, although the precise role it plays and its relationship to XPC remain to be elucidated. Here we show that XPC undergoes reversible ubiquitylation upon UV irradiation of cells and that this depends on the presence of functional UV-DDB activity. XPC and UV-DDB were demonstrated to interact physically, and both are polyubiquitylated by the recombinant UV-DDB-ubiquitin ligase complex. The polyubiquitylation altered the DNA binding properties of XPC and UV-DDB and appeared to be required for cell-free NER of UV-induced (6-4) photoproducts specifically when UV-DDB was bound to the lesion. Our results strongly suggest that ubiquitylation plays a critical role in the transfer of the UV-induced lesion from UV-DDB to XPC.
To examine the relationship between body mass index (BMI) and the risk of stage ≥3 chronic kidney disease (CKD) in a general Japanese population.
A total of 105 611 participants aged 40-79 years who ...completed health checkups in Ibaraki Prefecture, Japan, and were free of CKD in 1993 were followed-up through 2006. Stage ≥3 CKD was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m(2) reported during at least 2 successive annual surveys or as treatment for kidney disease. Hazard ratios (HRs) for the development of stage ≥3 CKD relative to the BMI categories were calculated using the Cox proportional hazards regression model, which was adjusted for possible confounders and mediators.
During a mean follow-up of 5 years, 19 384 participants (18.4%) developed stage ≥3 CKD. Compared to a BMI of 21.0-22.9 kg/m(2), elevated multivariable-adjusted HRs were observed among men with a BMI ≥23.0 kg/m(2) and women with a BMI ≥27.0 kg/m(2). Significant dose-response relationships between BMI and the incidence of stage ≥3 CKD were observed in both sexes (P for trend <0.001).
Obesity was associated with the risk of developing stage ≥3 CKD among men and women.
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