A range of age-related metabolic diseases may be prevented by lowering the levels of certain proteins called “fatty acid-binding proteins.”
Metabolic health may be preserved well into old age, a new study suggests, if we keep fatty acid-binding protein (FABP) levels very low.
In the new study, researchers from the Harvard T.H.
Chan School of Public Health in Boston, MA, altered levels of these proteins in mice in an attempt to see whether doing so would promote metabolic health, and, implicitly, lifespan.
Chan School of Public Health, and the findings were published in the journal Cell Reports.
Why study FABPs?
The study found that insufficient FABP levels “extended metabolic healthspan, [protecting] against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease.”
But “surprisingly,” write the authors, “FABP-deficient mice did not [show] any extension of lifespan.”
In other words, the mice shared many similarities with rodents that had undergone calorie restriction.
Therefore, some of the cardiometabolic benefits of calorie restriction could be selectively replicated by targeting FABPs.
To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks.
However, CAST overexpression significantly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively.
Furthermore, calpain inhibition suppressed macrophage migration to adipose tissue in vitro.
Abundance of calpain protein and its activity was increased in obese adipose tissue.
(A) Calpain-1, -2, -4, CAST and β-actin protein were detected by Western blotting in epididymal white adipose tissue (EpiWAT) extracts of wild type mice fed either a LFD or HFD for 16 weeks (n = 3).
(A) Representative TUNEL staining of EpiWAT cross-sections from 16 week LFD and HFD fed CAST WT and Tg mice.
(B) Representative EpiWAT sections from LFD and HFD fed CAST WT and Tg mice immunostained for active caspase 3.
(A) Representative immunofluorescent staining of F4/80 in EpiWAT cross-sections from 16 week LFD and HFD fed CAST WT and Tg mice.
(A) Representative Sirius red staining of EpiWAT cross-sections from LFD and HFD fed CAST WT and Tg mice.
(A) Representative hematoxylin and eosin staining of liver cross-sections from LFD and HFD fed CAST WT and Tg mice.
Moreover, elevated VLDLR protein was detected in CD11b+ ATMs from obese adipose tissues (Fig.
These data suggested that macrophage VLDLR could potentiate M1-like macrophage polarization by uptaking VLDL.
Although it has been shown that elevated circulating ceramides would confer systemic insulin resistance40, 41, the levels of secreted ceramides were not different in CM from WT and VLDLR KO BMDMs (Supplementary Fig. In WT macrophages, the level of C16:0 ceramides was elevated by VLDL, whereas VLDLR KO macrophages did not increase C16:0 ceramides in the presence of VLDL (Fig.
In the presence of VLDL, the levels of iNOS, TNFα, and IL-1β mRNA were less increased in VLDLR KO macrophages than WT macrophages (Fig.
Together, these data indicated that macrophage VLDLR could potentiate adipose tissue inflammation in DIO.
c, d Relative mRNA levels of macrophage (c) and pro-inflammatory (d) markers in EATs from WT and KO BMT mice.
These data imply that macrophage VLDLR would be important for potentiating M1-like macrophage polarization in the presence of VLDL.
iCCA cells express high levels of Fas and FasL that increase after co-culture with PBMCs inducing apoptosis in CD4+, CD8+ T-cells and in CD56+ NK-cells.
In vitro, c-FLIP is expressed in iCCA cells and the co-culture with PBMCs induces an increase of c-FLIP in both iCCA cells and biliary tree stem cells.
With this background, the aims of the present study were to investigate: (i) the expression of Fas and FasL in primary cultures isolated from human iCCA; (ii) the in vitro interactions between CCA cells and human PBMCs and the role of Fas/FasL in inducing T-cells and NK cells apoptosis; (iii) in situ the expression of Fas and FasL in human iCCA and their relationship with typical markers of CSC.
Evaluation of Fas and FasL in intrahepatic cholangiocarcinoma (iCCA) cells.
(A) Western Blot analysis of Fas and FasL performed on iCCA cells cultured alone and after 24, 48 and 72 h of co-culture with PBMCs; histograms represent mean ± SD; *P < 0.05, **P < 0.01, ***P < 0.001; §P < 0.05 iCCA co-cultured with PBMCs versus iCCA cells cultured alone at the same time points.
(B) Western Blot analysis of PCNA and NF-kB p65 in mixed- and mucin-iCCA cells cultured alone and after co-culture with PBMCs.
(A) Western blot analysis of c-FLIP, FADD, pro-caspase 8 and cleaved caspase 3 performed on iCCA cells cultured alone and on iCCA cells after 24, 48 and 72 h of co-culture with PBMCs.
Actin bands were presented as control of protein loading; histograms represent mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001 iCCA cells co-cultured with PBMCs versus iCCA cells cultured alone at the same time points.
Full size image Bcl-2 expression by intrahepatic cholangiocarcinoma (iCCA) cells.
(B) Confocal analysis and pseudocolor images of Bcl-2 expression in iCCA cells cultured alone and after co-culture with PBMCs at 24 h. Scale bar = 10 µm.
Postoperative neutrophil-to-lymphocyte ratio change (NLRc) reflects the dynamic change of balance between host inflammatory response and immune response after treatment.
The analysis revealed a higher predictive power for correlating patient survival with the NLRc compared with iNLR.
The NLRc could be a better indicator than iNLR for predicting survival in patients with gastric cancer.
Scatter plot of lymphocytes and neutrophils.
Full size image Disease-free and overall survival analysis according the initial neutrophil-to-lymphocyte ratio (iNLR) (a,b) and postoperative neutrophil-to-lymphocyte ratio change (NLRc) (c,d).
Full size image Postoperative neutrophil-to-lymphocyte ratio change (NLRc) reflects the dynamic change of balance between host inflammatory response and immune response after treatment.
The analysis revealed a higher predictive power for correlating patient survival with the NLRc compared with iNLR.
The NLRc could be a better indicator than iNLR for predicting survival in patients with gastric cancer.
Scatter plot of lymphocytes and neutrophils.
Full size image Disease-free and overall survival analysis according the initial neutrophil-to-lymphocyte ratio (iNLR) (a,b) and postoperative neutrophil-to-lymphocyte ratio change (NLRc) (c,d).
