Regulating Plasma Lipid Research Articles

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis

An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. To investigate the physiological role of (P)RR in lipid metabolism in vivo. We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

Lipid transfers to HDL are diminished in long-term bedridden patients: association with low HDL-cholesterol and increased inflammatory markers.

Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long-term care (>90days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193±36 vs 160±43, p=0.005), LDL (124±3 vs 96±33 p=0.003) and HDL-cholesterol (45±10 vs 36±13, p=0.008), apolipoprotein A-I (134±20 vs 111±24, p=0.001) and oxidized LDL (53±13 vs 43±12, p=0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL-cholesterol levels. Concentrations of IL-1β, IL-6, IL-8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL-cholesterol, apolipoprotein A-I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition.

Gelidium amansii ethanol extract suppresses fat accumulation by down-regulating adipogenic transcription factors in ob/ob mice model.

The purpose of this study was to determine the anti-obesity effects of Gelidium amansii extract (GAE) in the C57BL/6J-ob/ob mice. The ob/ob mice were fed GAE at 0.5% for 4 weeks, after which body weight, epididymal adipose tissue weight, plasma triglycerides, and hepatic lipid accumulation were significantly reduced in GAE-fed mice compared with ob/ob control mice. Plasma adiponectin levels were significantly higher in GAE-fed mice than in ob/ob control mice. These findings were supported by the expression levels of enzymes and proteins related to lipid metabolism assessed by western blotting: protein expression levels of the peroxisome proliferator-activated receptor γ and CCATT/enhancer binding protein α decreased significantly, while hormone-sensitive lipase and phospho-AMP-activated protein kinase levels increased in the GAE-fed mice compared with ob/ob control mice. These findings demonstrate that GAE regulates plasma lipid profiles and increasing highdensity lipoprotein cholesterol levels as well as by regulating the expression levels of lipid metabolic factors, resulting in reduced weight gain in ob/ob mice.

Association of apolipoprotein E polymorphism with plasma lipid disorders, independent of obesity-related traits in Vietnamese children.

BackgroundThe dyslipidemia associated with obesity plays a major role in the development of atherosclerosis and cardiovascular disease. Dyslipidemia in childhood can progress in adult stage. APOE is one of the most important genes that regulate plasma lipid transport and clearance. The study aimed to assess whether the common APOE polymorphism is associated with lipid profiles and dyslipidemia, and it could be modulated by obesity-related traits (body mass index, waist circumference, hip circumference, and waist-to-hip ratio) in Vietnamese children.MethodsA case-control study was designed including 249 cases with dyslipidemia and 600 controls without dyslipidemia. Dyslipidemia is defined as elevated total or low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol. Genotype for APOE polymorphism (rs7412 and rs429358) was determined by the polymerase chain reaction and restriction fragment length polymorphism method. The association of APOE genotypes with plasma lipid disorders was tested by binary logistic regression analysis, taking into account the confounding factors of age, sex, residence, province and obesity-related traits.ResultsIn comparison with ε3/ε3 carriers, the ε4 carriers had the highest concentration of serum TC and LDL-C in cases and controls (P ≤ 0.001), while ε2 carriers had the lowest. Carriers without TT haplotype had higher serum TC than those with TT haplotype. The ε4 carriers had higher hypoalphalipoproteinemia risk than ε3/ε3 carriers (OR = 2.78, P = 0.02) before and after adjustment for age, gender, residence and obesity-related traits.ConclusionsThe study suggested that the APOE genotype and haplotype significantly associated with plasma TC and LDL-C level in Vietnamese children. The association of APOE genotype with hypoalphalipoproteinemia was independent of obesity-related traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0349-6) contains supplementary material, which is available to authorized users.

The role of ANGPTL3 in controlling lipoprotein metabolism

Angiopoietin-like protein 3 (ANGPTL3) is a secretory protein regulating plasma lipid levels via affecting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids. ANGPTL3-deficiency due to loss-of-function mutations in the ANGPTL3 gene causes familial combined hypobetalipoproteinemia (FHBL2, OMIM # 605019), a phenotype characterized by low concentration of all major lipoprotein classes in circulation. ANGPTL3 is therefore a potential therapeutic target to treat combined hyperlipidemia, a major risk factor for atherosclerotic coronary heart disease. This review focuses on the mechanisms behind ANGPTL3-deficiency induced FHBL2.

Does myeloid expression of TRIB1 regulate plasma lipid levels

Aim: TRIB1 is a pseudokinase and recent GWAS analyses have linked this gene to the control of lipid homeostasis. Analysis of full body TRIB1 knockout and a liver specific TRIB1 overexpressing mouse have demonstrated that hepatic expression of TRIB1 reduces VLDL production, plasma triglycerides and cholesterol. Additionally, TRIB1 has been shown to be necessary for the development of M2 tissue macrophages. However, the interplay between TRIB1, macrophages and hepatocytes is unexplored.

Hepatocyte β-Klotho regulates lipid homeostasis but not body weight in mice.

β-Klotho (β-Kl), a transmembrane protein expressed in the liver, pancreas, adipose tissues, and brain, is essential for feedback suppression of hepatic bile acid synthesis. Because bile acid is a key regulator of lipid and energy metabolism, we hypothesized potential and tissue-specific roles of β-Kl in regulating plasma lipid levels and body weight. By crossing β-kl(-/-) mice with newly developed hepatocyte-specific β-kl transgenic (Tg) mice, we generated mice expressing β-kl solely in hepatocytes (β-kl(-/-)/Tg). Gene expression, metabolomic, and in vivo flux analyses consistently revealed that plasma level of cholesterol, which is over-excreted into feces as bile acids in β-kl(-/-), is maintained in β-kl(-/-) mice by enhanced de novo cholesterogenesis. No compensatory increase in lipogenesis was observed, despite markedly decreased plasma triglyceride. Along with enhanced bile acid synthesis, these lipid dysregulations in β-kl(-/-) were completely reversed in β-kl(-/-)/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in β-kl(-/-) mice were not reversed by hepatocyte-specific restoration of β-Kl expression. We conclude that β-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic β-Kl regulates energy metabolism. We further demonstrate that in a condition with excessive cholesterol disposal, a robust compensatory mechanism maintains cholesterol levels but not triglyceride levels in mice.

Trial Watch: Antisenses working overtime in lipids.

Antisense oligonucleotides have proven effective at preventing protein synthesis as a result of their on-target specificity. Recent data from several clinical trials including a phase I trial targeting Lp(a), published in The Lancet, highlight the therapeutic potential of antisense oligonucleotides in regulating plasma lipid levels.

The effects of isoflavones on lipid profile and oxidative stress in diabetic rats

Objective To investigate the effects of soybean isoflavone(SI) regulating plasma lipid and improving antioxidant ability in diabetic rats. Methods 120 SD rats were randomly devided into a normal group, a diabetes model group, a SI 40, 80, 160 and 320 mg/kg treated group, with 20 expermental animals in each group. Expect the normal group, the diabetic model was setup by intraperitoneal injecting STZ, and the drugs were given by intraperitoneal injection. At 0, 14, 28, 42, 56 days after experiment, the level of plasma glucose were determined. 8 weeks later, the content of TC, TG, LDL-C, HDL-C, the activity of AST, CK, LDH and the T-AOC in serum were determined; the activity of SOD, GSH-Px and the content of MDA in myocardial tissue were determined; and the histopathological changes of myocardial tissue were observed by HE staining. Results Compared with the diabetes model control group, the activity of AST in serum of SI 80, 160 and 320 mg/kg treated groups were significantly decreased(104.25 ± 24.92 U/L, 93.71 ± 22.58 U/L, 88.26 ± 23.80 U/L vs. 127.65 ± 38.17 U/L; P<0.05, P<0.01), the activity of CK were significantly decreased (887.1 ± 185.4 U/L, 831.9 ± 182.8 U/L, 796.2 ± 165.8 U/L vs. 973.6 ± 211.4 U/L; P<0.05, P<0.01), the activity of LDH were significantly decreased (954.7 ± 153.5 U/L, 868.7 ± 136.2 U/L, 834.1 ± 146.3 U/L vs. 1 097.6 ± 184.2 U/L; P<0.05, P<0.01); the activity of SOD in myocardial tissue were significantly increased(9.96 ± 2.05 U/mg, 10.47 ± 2.32 U/mg, 11.06 ± 2.29 U/mg vs. 8.72 ± 1.70 U/mg; P<0.05, P<0.01), the content of MDA in myocardial tissue were significantly decreased(5.98 ± 1.35 nmol/mg, 5.47 ± 1.42 nmol/mg, 5.16 ± 1.53 nmol/mg vs. 6.58 ± 1.54 nmol/mg; P<0.05, P<0.01). The plasma glucose level of SI (160 and 320 mg/kg) treated groups were significantly decreased(15.2 ± 0.9 mmol/L, 14.8 ± 0.8 mmol/L vs. 18.6 ± 1.2 mmol/L; P<0.05, P<0.01), the content of TC in serum were significantly decreased (2.69 ± 0.85 mmol/L, 2.43 ± 0.76 mmol/L vs. 3.42 ± 0.81 mmol/L; P<0.05, P<0.01), the content of TG were significantly decreased (1.36 ± 0.40 mmol/L, 1.18 ± 0.23 mmol/L vs. 1.70 ± 0.53 mmol/L; P<0.05, P<0.01), the content of LDL-C were significantly decreased (1.02 ± 0.26 mmol/L, 0.95 ± 0.28 mmol/L vs. 1.18 ± 0.27 mmol/L; P<0.05), and the content of HDL-C were significantly increased (0.73 ± 0.20 mmol/L, 0.78 ± 0.22 mmol/L vs. 0.62 ± 0.14 mmol/L; P<0.05), the T-AOC was significantly increased (10.15 ± 2.76 U/L, 11.29 ± 3.47 U/L vs. 7.95 ± 2.26 U/L; P<0.05), and the activity of GSH-Px was significantly increased(13.79 ± 2.62 U/mg, 14.21 ± 2.87 U/mg vs. 11.90 ± 2.03 U/mg，P<0.05, P<0.01). The histopathological changes of myocardial tissue in SI 160 and 320 mg/kg treated groups were significantly improved. Conclusions SI could effectively lower the plasma glucose level and the blood lipid, improve antioxidant ability, improve antioxidant ability, reduce the damage of free radical, and inhibit the histopathological changes, which suggesting that SI had protective effects on diabetic rats. Key words: Soybean isoflavone; Diabetes; Regulating plasma lipid; Antioxidant

Does myeloid expression of TRIB1 regulate plasma lipid levels?

Does myeloid expression of TRIB1 regulate plasma lipid levels?

Abstract 539: Oxidized Linoleic Acid Modulates Plasma Lipids and Associated Apolipoproteins in C57bl Mice

Introduction: Dietary oxidized lipids have been suggested to contribute to atherosclerosis. We have previously shown that oxidized linoleic acid (OxLA) modulates plasma lipids, feeding C57BL mice oxidized linoleic acid resulted in decreased plasma triglycerides and increased HDL. The current study is designed to investigate the mechanisms involved in the regulation of plasma lipids by the OxLA. Experimental Design: C57BL6 male mice (N=40) were divided into four groups (n = 10 each): Animals were fed for two months three different formulated diet except for the plain control (P) which was kept on normal mouse. The other three groups were as follows: control group supplemented with 18 mg/animal/day of linoleic acid (LA) (C); experimental group feed low concentration (9 mg/animal/day) of OxLA (A), and experimental group fed high dose of OxLA (18 mg/animal/day). After two months of feeding mice were sacrificed, blood, liver, and adipose tissues were collected for the analysis of plasma lipids, and related analyts and gene expressions for genes associated with lipoproteins metabolism. Results and Conclusion: The plasma total cholesterol and LDL have significantly (P&lt;0.007) decreased in the high concentration OxLA compared to the group fed LA; this was accompanied with decreases in the high concentration OxLA plasma TG although is not significant. There were no observed significant differences in the plasma lipids between the plain control and the OxLA high dose, and between the controls on LA and the low concentration OxLA. We have observed a significant dose dependent decreases in plasma ApoC3 in mice fed low OxLA (P&lt;0.01) and high OxLA (P&lt;0.003) compared to the control group on LA. Plasma lipase levels have shown similar trends; decreasing significantly (P&lt;0.04) in the OxLA groups compared to the plain controls. Plasma ApoA5 levels on the other hand greatly increased in high OxLA, LA, and low OxLA compared to plain group although is not significant. This study demonstrate that oxidized linoleic acid modulate plasma lipoprotein metabolism in mice through a likely ApoC3/lipase dependent mechanism(s).

Human plasma lipid modulation in schistosomiasis mansoni depends on apolipoprotein E polymorphism.

BackgroundSchistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE) gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis.Methodology/Principal FindingsBlood samples were used for APOE genotyping and to measure total cholesterol (TC), LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; P<0.0001) compared to control individuals, whereas HDL-C was increased (10% higher; P = 0.0136). Frequency of the common alleles, ε2, ε3 and ε4, was similar (P = 0.3568) between controls (n = 108) and patients (n = 84), implying that APOE genotype did not affect susceptibility to the advanced stage of schistosomiasis. Nevertheless, while patient TC and LDL-C levels were significantly reduced for each allele (except TC in ε2 patients), changes in HDL-C and triglycerides were noted only for the less common ε2 and ε4 alleles. The most striking finding, however, was that accepted regulation of plasma lipid levels by APOE genotype was disrupted by schistosomiasis. Thus, while ε2 controls had higher TC and LDL-C than ε3 carriers, these parameters were lower in ε2 versus ε3 patients. Similarly, the inverse relationship of TG levels in controls (ε2>ε3>ε4) was absent in patients (ε2 or ε4>ε3), and the increase in HDL-C of ε2 or ε4 patients compared to ε3 patients was not seen in the control groups.Conclusion/SignificanceWe confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

Exome sequencing: new insights into lipoprotein disorders.

Several next generation sequencing platforms allow for a DNA-to-diagnosis protocol to identify the molecular basis of monogenic dyslipidemias. However, recent reports of the application of whole genome or whole exome sequencing in families with severe dyslipidemias have largely identified genetic variants in known lipid genes. To date, high-throughput DNA sequencing in families with previously uncharacterized monogenic dyslipidemias, have failed to reveal new genes for regulation of plasma lipids. This suggests that rather than sequencing whole genomes or exomes, most patients with monogenic dyslipidemias could be diagnosed using a more dedicated approach that focuses primarily on genes already known to act within lipoprotein metabolic pathways.

Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth.

BackgroundDiets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.Results The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.Conclusions These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.

CELSR2–PSRC1–SORT1 gene expression and association with coronary artery disease and plasma lipid levels in an Asian Indian cohort

BackgroundGenetic regulation of plasma lipids has been shown to influence the risk of coronary artery disease (CAD). We analyzed the relationship between rs599839 and rs646776 single nucleotide polymorphisms (SNPs) present in the CELSR2–PSRC1–SORT1 gene cluster, candidate gene expression, and their association with CAD and circulating lipid levels in a representative cohort of Asian Indians selected from the Indian Atherosclerosis Research Study. MethodsSNPs rs599839 and rs646776 were genotyped by Taqman assay in 1034 CAD patients (cases) and 1034 age- and gender-matched controls. Expression of CELSR2, PSRC1, and SORT1 genes was measured in 100 cases and 100 controls. Plasma levels of total cholesterol (TC), triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol (LDL-c) were measured by enzymatic assay. ResultsBoth rs646776 and rs599839 were in strong linkage disequilibrium (r=0.98) and showed significant protective association with CAD (OR=0.315, 95% CI 0.136–0.728, p<0.007 and OR=0.422, 95% CI 0.181–0.981, p=0.045, respectively). Haplotype TA showed 72% frequency and was associated with CAD (OR 0.77, 95% CI 0.67–0.88, p=0.0002). PSRC1 gene expression was lower in the cases than in the controls (0.75±0.405 versus 1.04±0.622, p=2.26×10−4). The homozygous variant and heterozygous genotypes showed 30% and 15% higher PSRC1 expression, respectively. Correspondingly, the minor alleles were associated with lower plasma TC and LDL-c levels. ConclusionPSRC1 in the cholesterol gene cluster shows a significant association with CAD by virtue of the two SNPs, rs646776 and rs599839 that also regulate plasma cholesterol levels.

Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans

The circadian system regulates daily rhythms in lipid metabolism and adipose tissue function. Although disruption of circadian clock function is associated with negative cardiometabolic end points, very little is known about interindividual variation in circadian-regulated metabolic pathways. Here, we used targeted lipidomics-based approaches to profile the time course of 263 lipids in blood plasma in 20 healthy individuals. Over a span of 28 h, blood was collected every 4 h and plasma lipids were analyzed by HPLC/MS. Across subjects, about 13% of lipid metabolites showed circadian variation. Rhythmicity spanned all metabolite classes examined, suggesting widespread circadian control of lipid-mediated energy storage, transport, and signaling. Intersubject agreement for lipids identified as rhythmic was only about 20%, however, and the timing of lipid rhythms ranged up to 12 h apart between individuals. Healthy subjects therefore showed substantial variation in the timing and strength of rhythms across different lipid species. Strong interindividual differences were also observed for rhythms of blood glucose and insulin, but not cortisol. Using consensus clustering with iterative feature selection, subjects clustered into different groups based on strength of rhythmicity for a subset of triglycerides and phosphatidylcholines, suggesting that there are different circadian metabolic phenotypes in the general population. These results have potential implications for lipid metabolism disorders linked to circadian clock disruption.

Polyunsaturated fatty acid relatively decreases cholesterol content in THP-1 macrophage-derived foam cell: partly correlates with expression profile of CIDE and PAT members

BackgroundPolyunsaturated fatty acids (PUFAs) have positive effect on the regulation of plasma lipids. But the mechanism for them to modulate lipid homeostasis in macrophage is still unclear. In this study, we employed PUFA to pretreat macrophages and evaluated the variations of lipid droplet (LD) content, lipid composition, and expressions of LD-associated genes in macrophage-derived foam cells.MethodTHP-1-derived macrophages or human peripheral blood monocyte-derived macrophages were pre-treated with four non-esterified fatty acids (NEFAs) separately: saturated fatty acid (SFA)-palmitic acid (PA), monounsaturated fatty acids (MUFAs)-oleic acid (OA), PUFAs-linoleic acid (LA) and eicosapentaenoic acid (EPA). Intracellular lipid content and cholesterol efflux were analyzed in THP-1 macrophage-derived foam cells. Related gene expressions were detected by quantitative real-time PCR.ResultsPUFA pre-treatment reduced cholesterol content in foam cells and increased cholesterol efflux to lipid-free apoAI in conditioned medium compared with PA or OA group. Cell death-inducing DFF45 like effector (CIDE) and Perilipin-Adipophilin-TIP47 (PAT) family members, as LD-associated proteins, showed specific gene expression profiles after PUFA pre-treatment. These results may help to explain the process of lipid metabolism within foam cells.ConclusionPUFA (LA or EPA) had a potential protective effect against cholesterol accumulation. The specific expressions of CIDE and PAT genes may provide clues to explore the protective mechanism of PUFA in foam cells.

The therapeutic potential of GPR43: a novel role in modulating metabolic health.

GPR43 is a receptor for short-chain fatty acids. Preliminary data suggest a putative role for GPR43 in regulating systemic health via processes including inflammation, carcinogenesis, gastrointestinal function, and adipogenesis. GPR43 is involved in secretion of gastrointestinal peptides, which regulate appetite and gastrointestinal motility. This suggests GPR43 may have a role in weight control. Moreover, GPR43 regulates plasma lipid profile and inflammatory processes, which further indicates that GPR43 could have the ability to modulate the etiology and pathogenesis of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. This review summarizes the current evidence regarding the ability of GPR43 to mediate both systemic and tissue specific functions and how GPR43 may be modulated in the treatment of metabolic disease.

Circadian Regulation of Intestinal Lipid Absorption by Apolipoprotein AIV Involves Forkhead Transcription Factors A2 and O1 and Microsomal Triglyceride Transfer Protein

We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.

Abstract 2: Circadian Regulation of Intestinal Lipid Absorption by ApoAIV Involves Forkhead Transcription Factors A2/O1 and MTP

Clock, MTP and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Total plasma triglyceride/cholesterol in ApoAIV -/- mice showed diurnal variations similar to ApoAIV +/+ mice; however, increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV -/- mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night and its induction after food entrainment was less in ApoAIV -/- mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2/FoxO1 transcription factors and their binding to the identified cis -elements in the MTP promoter at night. Knockdown of FoxA2/FoxO1 abolished apoAIV mediated MTP induction. Moreover, FoxA2/FoxO1 expression showed diurnal variations and their expressions were significantly lower in ApoAIV -/- mice. These data indicate that apoAIV modulates diurnal regulation of lipid absorption by regulating forkhead transcription factors and MTP, and that inhibition of apoAIV expression might reduce plasma lipids.