Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress.

BACKGROUND: Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies. AIM: To investigate whether and how AFP could regulate ER stress and hepatocyte injury. METHODS: The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence. RESULTS: High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CCl4) administration or induction of ER stress, but not from the controls. The induced intracellular AFP was accompanied by elevated activating transcription factor-6 (ATF6) expression and protein kinase R-like ER kinase (PERK) phosphorylation in mouse livers. ER stress induced AFP expression in LO2 cells and decreased their viability. ATF6, but not PERK, silencing mitigated the ER-stress-induced AFP expression in LO2 cells. Conversely, AFP silencing deteriorated the ER stress-mediated LO2 cell injury and CCl4 administration-induced liver damages by increasing levels of cleaved caspase-3, the C/enhancer binding protein homologous protein expression, mixed lineage kinase domain-like pseudokinase and PERK phosphorylation, but decreasing ATF6 expression. CONCLUSION: ER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.

Association between lipoproteins and telomere length in US adults: data from the NHANES 1999-2002.

BACKGROUND: Evidence regarding the correlation between lipoproteins and telomere length in US adults is limited. We aimed to investigate whether lipoproteins was associated with telomere length using US National Health and Nutrition Examination Survey (NHANES) database. METHODS: A total of 6468 selected participants were identified in the NHANES Data Base (1999-2002). The independent and dependent variables were lipoproteins and telomere length, respectively. The covariates included demographic data, dietary data, physical examination data, and comorbidities. RESULTS: In fully-adjusted model, we found that 0.1 differences of telomere length were positively associated with HDL-C [0.19 (95% CI 0.07, 0.31)], while the associations between LDL-C [0.19 (95% CI -0.27, 0.65)], TG [- 1.00 (95% CI -2.09, 0.07) and telomere length were not detected. By nonlinearity test, only the relationship between HDL-C and telomere length was nonlinear. The inflection point we got was 1.25. On the left side of the inflection point (telomere length ≤ 1.25), a difference in 0.1 of telomere length was associated with 0.50 difference in HDL-C. CONCLUSION: After adjusting for demographic data, dietary data, physical examination data, and comorbidities, telomere length is not associated with LDL-C and TG, but is positively associated with HDL-C when telomere length is less than 1.25.

Estimated glomerular filtration rate and arterial stiffness in Japanese population: a secondary analysis based on a cross-sectional study.

BACKGROUND: Evidence regarding the relationship between estimated glomerular filtration rate (eGFR) and arterial stiffness is limited, and the data analysis is not sufficient to clarify the true relationship between the two. We aimed to investigate the relationship between eGFR and brachial-ankle pulse wave velocity (baPWV) in Japanese. METHODS: The present study was a cross-sectional study. Nine hundred twelve Japanese men and women, aging 24-84 years old, received a health medical check-up program including the results from baPWV inspection and various standardized questionnaires in a health examination center in Japan. The main outcome measures included eGFR, baPWV, fatty liver and postmenopausal status. Abdominal ultrasonography was used to diagnose fatty liver. Postmenopausal state was defined as beginning 1 year after the cessation of menses. RESULTS: The average age of the 912 selected participants was 51.5 ± 9.6 years old, and about 57.6% of them were male. The participants' eGFR distribution was median 69.29 (min 39, max 122.28). The results of multivariate linear regression showed eGFR was not independently associated with baPWV after adjusting potential confounders (ß = - 1.11, 95%CI -2.25 to 0.03), this is inconsistent with the result of eGFR (quartile) as a categorical variable (p for trend was 0.038). A non-linear relationship was detected between eGFR and baPWV, whose point was 77.05. The effect sizes and the confidence intervals of the left and right sides of inflection point were - 2.80 (- 4.41 to - 1.19) and 1.84 (- 0.50, 4.17), respectively. Subgroup analysis showed, the change in the elderly population is more pronounced (P for interaction = 0.018; - 2.83 with ≤60 year vs - 6.12 with > 60 year). The same trend was also seen in hypertensive people (P for interaction = 0.018; - 4.55 with hypertension vs - 0.82 with non-hypertension). CONCLUSION: The relationship between eGFR and baPWV is non-linear. eGFR was negatively related to baPWV when eGFR is less than 77.05.