PubMed | The Chaim Sheba Medical Center, The Bert rassburger Lipid Center and Tel Aviv University
Type: Journal Article | Journal: Obesity surgery | Year: 2015
The lymphatic system is responsible for the absorption of fats from the digestive system, conveying 60-70 % of ingested fat to the blood stream. From the anatomical point of view, all the lymphatic drainage from the lower half of the body converges in the abdomen to enter the thoracic duct. This experimental study aim was to study the result of thoracic duct narrowing (TDN), an innovative surgical technique, on weight gain restrain in high-fat diet-fed rats.Forty-seven rats were allocated into three groups: thoracic duct narrowing (S-surgery), sham operation (CS-control surgery), and no surgery (C-control). All rats were fed with high-fat, cholesterol-rich diet. Food consumption and metabolic syndrome parameters including weight gain, plasma lipids and glucose, blood pressure, and viscera weight and histopathology were analyzed.Thoracic duct narrowing was proved simple and safe surgical procedure in the rat model. TDN induced weight gain restrain, associated with mild hepatic steatosis compared to moderate-severe hepatic steatosis in control groups. Splenomegaly and splenic fatty histiocytes were shown in the treated animals.TDN improved several parameters of the metabolic syndrome in high-fat diet-fed rats. TDN carries the potential of innovative obesity treatment using the lymphatic route of lipid absorption.
PubMed | N.B.T., The Bert rassburger Lipid Center, Tel Aviv University and Debrecen University
Type: | Journal: BioMed research international | Year: 2015
Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE(-/-)). ApoE(-/-) mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing c isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary c fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary c, as a sole source of retinoids, can compensate for vitamin A deficiency.
PubMed | Artery Inc., Lawrence Berkeley National Laboratory, The Bert rassburger Lipid Center and Tel Aviv University
Type: Journal Article | Journal: PloS one | Year: 2016
Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimers disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.
PubMed | N.B.T. and The Bert rassburger Lipid Center
Type: Journal Article | Journal: Nutrients | Year: 2016
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis--carotene (9-cis-c) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-c increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with c from the alga Dunaliella led to c accumulation in peritoneal macrophages. 9-cis-c increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from c in RAW264.7 macrophages. Furthermore, 9-cis-c, as well as all-trans-c, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-c augmented cholesterol efflux from macrophages ex vivo. 9-cis-c increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-c from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of c in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.
Grosskopf I.,The Bert rassburger Lipid Center |
Grosskopf I.,Tel Aviv Sourasky Medical Center |
Shaish A.,The Bert rassburger Lipid Center |
Afek A.,Institute of Pathology |
And 6 more authors.
Atherosclerosis | Year: 2012
Objective: Apolipoprotein A-V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA-V would inhibit atherogenesis in apoE-/- mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. Methods and results: ApoA-V+/+ApoE-/- mice expressing human apolipoprotein A-V (hapoA-V) were generated and compared to apoE-/- mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA-V+/+apoE-/-. This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA-V+/+apoE-/- mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA-V+/+apoE-/- mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA-V+/+apoE-/- mice. In addition, hapoA-V+/+apoE-/- mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA-V+/+apoE-/- displayed a milder systemic inflammatory response compared to apoE-/- mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. Conclusions: We showed that human apolipoprotein A-V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA-V as a potential therapeutic target for treatment of atherosclerosis. © 2012 Elsevier Ireland Ltd.
Shemesh S.,The Bert rassburger Lipid Center |
Shemesh S.,Bar - Ilan University |
Kamari Y.,The Bert rassburger Lipid Center |
Kamari Y.,Tel Aviv University |
And 9 more authors.
Atherosclerosis | Year: 2012
Objectives: Interleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1α and IL-1β are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1's effects in atherogenesis. Methods and results: We generated apoE-/-/IL-1R1-/- double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20-47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1α and IL-1β upon stimulation with LPS was not altered in IL-1R1-/- compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules and IL-1α, in isolated human umbilical vein endothelial cells (HUVEC). Conclusions: Vascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells. © 2011 Elsevier Ireland Ltd.
PubMed | Genetics and Genomic science, The Bert rassburger Lipid Center and Tel Aviv University
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Oocyte endowment dwindles away during prepubertal and adult life until menopause occurs, and apoptosis has been identified as a central mechanism responsible for oocyte elimination. A few recent reports suggest that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the proinflammatory cytokine IL-1 in the age-related exhaustion of ovarian reserve using IL-1 and IL-1-KO mice. IL-1-KO mice showed a substantially higher pregnancy rate and litter size compared with WT mice at advanced age. The number of secondary and antral follicles was significantly higher in 2.5-mo-old IL-1-KO ovaries compared with WT ovaries. Serum anti-Mllerian hormone, a putative marker of ovarian reserve, was markedly higher in IL-1-KO mice from 2.5 mo onward, along with a greater ovarian response to gonadotropins. IL-1-KO mice displayed a comparable but more subtle prolongation of ovarian lifespan compared with IL-1-KO mice. The protein and mRNA of both IL-1 and IL-1 mice were localized within the developing follicles (oocytes and granulosa cells), and their ovarian mRNA levels increased with age. Molecular analysis revealed decreased apoptotic signaling [higher B-cell lymphoma 2 (BCL-2) and lower BCL-2-associated X protein levels], along with a marked attenuation in the expression of genes coding for the proinflammatory cytokines IL-1, IL-6, and TNF- in ovaries of IL-1-KO mice compared with WT mice. Taken together, IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve in mice, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.
PubMed | The Bert rassburger Lipid Center, Tel Aviv University and Ben - Gurion University of the Negev
Type: Journal Article | Journal: Cytokine | Year: 2015
IL-1 and IL-1 are synthesized as 31kDa cell-associated precursors following TLR-4 stimulation, but their processing to the mature form and secretion require a second intracellular stimulus. The unique localization of the precursor of IL-1 (pro-IL-1) to the nucleus suggested a role in transcriptional regulation of inflammatory cytokines. We explored the hypothesis that pro-IL-1 is involved in regulation of IL-1 expression following TLR-4 stimulation. IL-1 mRNA and protein levels were specifically decreased in macrophages from IL-1-deficient mice following TLR-1/2, TLR-4 or TLR-9 stimulation, supporting the hypothesis. However, activation of the main upstream regulators of IL-1 expression, IRF3, NFkB and p38/JNK, were not reduced in macrophages from IL-1-deficient mice. In order to assess the specific role of IL-1 in macrophages, we generated mice with myeloid cell deficiency of IL-1 (LyzMCre-loxp). Despite over 90% knockdown of IL-1, TLR-4 stimulated macrophages from LyzMCre-loxp mice did not produce lower levels of IL-1 compared to IL-1-loxp-flanked mice. In order to overcome the possibility that effects are caused by the incomplete deficiency of IL-1, we generated new whole-body IL-1 knockout mice (GeneralCre-IL-1) and the findings were similar to myeloid cell-deficient IL-1. Collectively, our findings do not support the previously suggested role of nuclear IL-1 in gene regulation of IL-1. Rather, they suggest that IL-1 acts mainly as an alarmin that is sequestered in the nucleus following stimulation with TLR-4.
PubMed | The Bert rassburger Lipid Center, Tel Aviv University and Sheba Medical Center
Type: Journal Article | Journal: Journal of hepatology | Year: 2015
ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1 is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1 is involved in ER stress-induced apoptosis and steatohepatitis.We employed WT and IL-1-deficient mice to study the role of IL-1 in ER stress-induced steatohepatitis.Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1 deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1 deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1, IL-6, TNF, and CHOP, with no effect on the degree of fatty liver formation. IL-1 was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1 mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1 deficient compared to WT mice. ER stress induced the expression of IL-1 and IL-1 also in mouse primary hepatocytes. Recombinant IL-1 treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1 and IL-1 mRNA levels.We show that IL-1 is upregulated in response to ER stress and IL-1 deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1 may contribute to the induction of CHOP intracellularly, while IL-1 released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.
PubMed | The Bert rassburger Lipid Center, Tel Aviv University and Ben - Gurion University of the Negev
Type: Journal Article | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2014
The role of Kupffer cell interleukin (IL)-1 in non-alcoholic steatohepatitis development remains unclear.To evaluate the role of Kupffer cell IL-1, IL-1 or IL-1 receptor type-1 (IL-1R1) in steatohepatitis.C57BL/6 mice were irradiated and transplanted with bone marrow-derived cells from WT, IL-1-/-, IL-1-/- or IL-1R1-/- mice combined with Kupffer cell ablation with Gadolinium Chloride, and fed atherogenic diet. Plasma and liver triglycerides and cholesterol, serum alanine aminotransferase (ALT), liver histology and expression levels of inflammatory genes were assessed.The ablation and replacement of Kupffer cells with bone marrow-derived cells was confirmed. The atherogenic diet elevated plasma and liver cholesterol, reduced plasma and liver triglycerides and increased serum ALT levels in all groups. Steatosis and steatohepatitis were induced, but without liver fibrosis. A reduction in the severity of portal inflammation was observed only in mice with Kupffer cell deficiency of IL-1. Accordingly, liver mRNA levels of inflammatory genes encoding for IL-1, IL-1, TNF, SAA1 and IL-6 were significantly lower in mice with Kupffer cell deficiency of IL-1 compared to WT mice.Selective deficiency of IL-1 in Kupffer cells reduces liver inflammation and expression of inflammatory cytokines, which may implicate Kupffer cell-derived IL-1 in steatohepatitis development.