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PurposeAngiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.MethodsFour groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose).ResultsCompared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB.ConclusionsChronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

PurposeAngiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.MethodsFour groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose).ResultsCompared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB.ConclusionsChronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

Phospholipase A2 (PLA2) enzymes influence inflammatory bowel disease in both positive and negative manners depending on the type of PLA2 that is expressed. This study explored the influence of the abundantly expressed Group 1B PLA2 (PLA2G1B) on ulcerative colitis. Wild-type C57BL/6J mice and Pla2g1b−/− mice were treated with dextran sulfate sodium (DSS) for 5 days to induce epithelial injury, followed by another 5 days without DSS for recovery. The Pla2g1b−/− mice displayed significantly less body weight loss, colitis pathology, and disease activity indexes compared to the wild-type mice. The differences in colitis were not due to differences in the colonic lysophospholipid levels, but higher numbers of stem and progenitor cells were found in the intestines of Pla2g1b−/− mice compared to the wild-type mice. The DSS-treated Pla2g1b−/− mice also showed higher expressions of genes that are responsible for epithelial repair and lower expressions of proinflammatory cytokine genes in the colon, as well as reduced inflammatory cytokine levels in the plasma. In vitro experiments revealed the PLA2G1B stimulation of inflammatory cytokine expression by myeloid cells. PLA2G1B inactivation protects against DSS-induced colitis in mice by increasing the intestinal stem cell reservoir for epithelial repair and reducing myeloid cell inflammation in the diseased colon. Thus, PLA2G1B may be a target for colitis management. [ABSTRACT FROM AUTHOR]

The gut microbiome plays an essential role in regulating lipid metabolism. However, little is known about how gut microbiome modulates sex differences in lipid metabolism. The present study aims to determine whether gut microbiota modulates sexual dimorphism of lipid metabolism in mice fed a high-fat diet (HFD). Conventional and germ-free male and female mice were fed an HFD for four weeks, and lipid absorption, plasma lipid profiles, and apolipoprotein levels were then evaluated. The gut microbiota was analyzed by 16S rRNA gene sequencing. After 4-week HFD consumption, the females exhibited less body weight gain and body fat composition and significantly lower triglyceride levels in very-low-density lipoprotein (VLDL) and cholesterol levels in high-density lipoprotein (HDL) compared to male mice. The fecal microbiota analysis revealed that the male mice were associated with reduced gut microbial diversity. The female mice had considerably different microbiota composition compared to males, e.g., enriched growth of beneficial microbes (e.g., Akkermansia) and depleted growth of Adlercreutzia and Enterococcus. Correlation analyses suggested that the different compositions of the gut microbiota were associated with sexual dimorphism in body weight, fat mass, and lipid metabolism in mice fed an HFD. Our findings demonstrated significant sex differences in lipid metabolism and the microbiota composition at baseline (during LFD), along with sex-dependent responses to HFD. A comprehensive understanding of sexual dimorphism in lipid metabolism modulated by microbiota will help to develop more sex-specific effective treatment options for dyslipidemia and metabolic disorders in females. [ABSTRACT FROM AUTHOR]

Introduction: Patients with systemic lupus erythematosus (SLE) are at elevated risk for Q10 cardiovascular disease (CVD) due to accelerated atherosclerosis. Compared to heathy control subjects, lupus patients have higher volumes and densities of thoracic aortic perivascular adipose tissue (PVAT), which independently associates with vascular calcification, a marker of subclinical atherosclerosis. However, the biological and functional role of PVAT in SLE has not been directly investigated. Methods: Using mouse models of lupus, we studied the phenotype and function of PVAT, and the mechanisms linking PVAT and vascular dysfunction in lupus disease. Results and discussion: Lupus mice were hypermetabolic and exhibited partial lipodystrophy, with sparing of thoracic aortic PVAT. Using wire myography, we found that mice with active lupus exhibited impaired endothelium-dependent relaxation of thoracic aorta, which was further exacerbated in the presence of thoracic aortic PVAT. Interestingly, PVAT from lupus mice exhibited phenotypic switching, as evidenced by "whitening" and hypertrophy of perivascular adipocytes along with immune cell infiltration, in association with adventitial hyperplasia. In addition, expression of UCP1, a brown/beige adipose marker, was dramatically decreased, while CD45-positive leukocyte infiltration was increased, in PVAT from lupus mice. Furthermore, PVAT from lupus mice exhibited a marked decrease in adipogenic gene expression, concomitant with increased pro-inflammatory adipocytokine and leukocyte marker expression. Taken together, these results suggest that dysfunctional, inflamed PVAT may contribute to vascular disease in lupus. [ABSTRACT FROM AUTHOR]

Ezetimibe is a potent inhibitor of cholesterol absorption by enterocytes. Although ezetimibe minimally affects the absorption of triglyceride, it is unknown whether ezetimibe affects the secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). It has been shown that ezetimibe-treated mice are protected from diet-induced insulin resistance. Since GIP and GLP-1 promote the actions of insulin, we hypothesized that ezetimibe may affect the secretion of GIP and GLP-1 by enteroendocrine cells into lymph in response to the intestinal absorption of a mixed meal (Ensure). To test this hypothesis, we used the lymph fistula rat model to determine GIP and GLP-1 concentrations in lymph during the 2 h after the infusion of Ensure. Ezetimibe significantly reduced lymphatic cholesterol output during fasting, without coincident decreases in glucose, protein, and triglyceride outputs. However, ezetimibe did not influence cholesterol output after infusion of Ensure. Interestingly, ezetimibe significantly reduced the secretion of both GIP and GLP-1 into lymph after the infusion of Ensure. Therefore, the inhibitory effect of ezetimibe on GIP and GLP-1 secretion by enteroendocrine cells occurs outside of the effects of glucose, protein, or triglyceride secretion by the intestine. cholesterol absorption; glucose-dependent insulinotropic polypeptide; glucagon-like peptide-1; lymph doi: 10.1152/ajpgi.00294.2010.

Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERα, direct ERα-Gαi interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERα- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer., Introduction Steroid hormone receptors (SHRs) function classically as transcription factors. More recently, it has become apparent that steroid hormones also initiate nongenomic responses via activation of a subpopulation of these [...]

The impact of NPC1L1 and ezetimibe on cholesterol absorption are well documented. However, their potential consequences relative to absorption and metabolism of other nutrients have been only minimally investigated. Thus studies were undertaken to investigate the possible effects of this protein and drug on fat absorption, weight gain, and glucose metabolism by using [Npc1l1.sup.-/-] and ezetimibe-treated mice fed control and high-fat, high-sucrose diets. Results show that lack of NPC1L1 or treatment with ezetimibe reduces weight gain when animals are fed a diabetogenic diet. This resistance to diet-induced obesity results, at least in part, from significantly reduced absorption of dietary saturated fatty acids, particularly stearate and palmitate, since food intake did not differ between groups. Expression analysis showed less fatty acid transport protein 4 (FATP4) in intestinal scrapings of [Npc1l1.sup.-/-] and ezetimibe-treated mice, suggesting an important role for FATP4 in intestinal absorption of long-chain fatty acids. Concomitant with resistance to weight gain, lack of NPC1L1 or treatment with ezetimibe also conferred protection against diet-induced hyperglycemia and insulin resistance. These unexpected beneficial results may be clinically important, given the focus on NPC1L1 as a target for the treatment of hypercholesterolemia. diabetogenic diet; glucose metabolism; insulin sensitivity; Western diet; sucrose polybehenate

Intestinal cholesterol absorption is modulated by transport proteins in enterocytes. Cholesterol uptake from intestinal lumen requires several proteins on apical brush-border membranes, including Niemann-Pick CI-like 1 (NPC1L1), scavenger receptor B-I, and CD36, whereas two ATP-binding cassette half transporters, ABCG5 and ABCG8, on apical membranes work together for cholesterol efflux back to the intestinal lumen to limit cholesterol absorption. NPCIL1 is essential for cholesterol absorption, but its function as a cell surface transporter or an intracellular cholesterol transport protein needs clarification. Another ATP transporter, ABCAI, is present in the basolateral membrane to mediate HDL secretion from enterocytes. Niemann-Pick C1-Like 1 protein; scavenger receptors; ATP-binding cassette proteins

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects [...]

Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which [...]

Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately [...]

Group 1B phospholipase [A.sub.2] (PL[A.sub.2]) is an abundant lipolytic enzyme that is well characterized biochemically and structurally. Because of its high level of expression in the pancreas, it has been presumed that PL[A.sub.2] plays a role in the digestion of dietary lipids, but in vivo data have been lacking to support this theory. Our initial study on mice lacking PL[A.sub.2] demonstrated no abnormalities in dietary lipid absorption in mice consuming a chow diet. However, the effects of PL[A.sub.2] deficiency on animals consuming a high-fat diet have not been studied. To investigate this, PL[A.sub.2.sup.+/+] and PL[A.sub.2.sup.-/-] mice were fed a western diet for 16 wk. The results showed that PL[A.sub.2.sup.+/+] mice were resistant to high-fat diet-induced obesity. This observed weight difference was due to decreased adiposity present in the PL[A.sub.2.sup.-/-] mice. Compared with PL[A.sub.2.sup.+/+] mice, the PL[A.sub.2.sup.-/-] mice had 60% lower plasma insulin and 72% lower plasma leptin levels after high-fat diet feeding. The PL[A.sub.2.sup.-/-] mice also did not exhibit impaired glucose tolerance associated with the development of obesity-related insulin resistance as observed in the PL[A.sub.2.sup.+/+] mice. To investigate the mechanism by which PL[A.sub.2.sup.-/-] mice exhibit decreased weight gain while on a high-fat diet, fat absorption studies were performed. The PL[A.sub.2.sup.-/-] mice displayed 50 and 35% decreased plasma [[sup.3]H]triglyceride concentrations 4 and 6 h, respectively, after feeding on a lipid-rich meal containing [[sup.3]H]triolein. The PL[A.sub.2.sup.-/-] mice also displayed increased lipid content in the stool, thus indicating decreased fat absorption in these animals. These results suggest a novel role for PL[A.sub.2] in the protection against diet-induced obesity and obesity-related insulin resistance, thereby offering a new target for treatment of obesity and diabetes. phospholipase As; lipase; pancreatic enzymes; animal models; lipid absorption

Results demonstrate that apolipoprotein E inhibition of smooth muscle cell proliferation occurs via its binding to heparan sulfate proteoglycans. The cell migration inhibition is brought about by its binding to the low-density lipoprotein receptor related protein.