Apolipoprotein M

Apolipoprotein M (apoM) is a 26-kDa protein that is mainly associated with high-density lipoprotein (HDL) in human plasma, with a small proportion present in triglyceride-rich lipoproteins (TGRLP) and low-density lipoproteins (LDL). Human apoM gene is located in p21.31 on chromosome 6 (chromosome 17, in mouse). Human apoM cDNA (734 base pairs) encodes 188-amino acid residue-long protein. It belongs to lipocalin protein superfamily. Human tissue expression array study indicates that apoM is only expressed in liver and in kidney and small amounts are found in fetal liver and kidney. In situ apoM mRNA hybridization demonstrates that apoM is exclusively expressed in the hepatocytes and in the tubule epithelial cells in kidney. Expression of apoM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF) and leptin in vivo and/or in vitro. It has been demonstrated that apoM expression is dramatically decreased in apoA-I deficient mouse. Hepatocyte nuclear factor-1α (HNF-1α) is an activator of apoM gene promoter. Deficiency of HNF-1α mouse shows lack of apoM expression. Mutations in HNF-1α (MODY3) have reduced serum apoM levels. Expression of apoM is significantly decreased in leptin deficient (ob/ob) mouse or leptin receptor deficient (db/db) mouse. ApoM concentration in plasma is positively correlated to leptin level in obese subjects. These may suggest that apoM is related to the initiation and progression of MODY3 and/or obesity

Influence of liver cancer on lipid and lipoprotein metabolism

Liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. This has been attributed to the high incidence of hepatitis B infection. Hepatitis B proteins, such as the hepatitis B X protein (HBx) that is large hepatitis B surface protein could regulate transcription of many candidate genes for liver carcinogenesis. It has known that patients who suffered from acute hepatitis B could have lipid disorders such as decreased plasma level of high-density lipoproteins (HDL). Furthermore, aberrations of lipid metabolism are often seen in the chronic hepatitis B infection. Plasma lipid profiles could be changed under HCC. In majority of the reports in HCC, plasma levels of triglycerides (TG), cholesterol, free fatty acids (FFA), HDL, low-density lipoproteins (LDL), lipoprotein (a) (Lp(a)), apolipoprotein AI (apoAI) and apoB were slight to significantly decreased, however, in some cases plasma levels of TG and Lp(a) might be increased. It has been suggested that analysis of plasma levels of lipids, lipoproteins and apolipoproteins in the patients suffered from HCC reflects on the hepatic cellular impairment status. Studies revealed that alterations seen in the plasma levels of lipids, lipoproteins and apolipoproteins reflecting patients' pathologic conditions. Decreased serum levels of cholesterol and apoAI may indicate a poor prognosis. Human leukaemic cells and certain tumor tissues have a higher receptor-mediated uptake of HDL and LDL than the corresponding normal cells or tissues. LDL and HDL have therefore been proposed as a carrier for the water-insoluble anti-cancer agents

Lipid synthesis and secretion in HepG2 cells is not affected by ACTH

Apolipoprotein B (apoB) containing lipoproteins, i.e. VLDL, LDL and Lp(a), are consequently lowered by ACTH treatment in humans. This is also seen as reduced plasma apoB by 20-30% and total cholesterol by 30-40%, mostly accounted for by a decrease in LDL-cholesterol. Studies in hepatic cell line (HepG2) cells showed that apoB mRNA expression is reduced in response to ACTH incubation and is followed by a reduced apoB secretion, which may hypothesize that ACTH lowering apoB containing lipoproteins in humans may be mediated by the inhibition of hepatic apoB synthesis. This was recently confirmed in vivo in a human postprandial study, where ACTH reduced transient apoB48 elevation from the small intestine, however, the exogenic lipid turnover seemed unimpaired. In the present study we investigated if lipid synthesis and/or secretion in HepG2 cells were also affected by pharmacological levels of ACTH to accompany the reduced apoB output. HepG2 cells were incubated with radiolabelled precursors ([14C]acetate and [3H]glycerol) either before or during ACTH stimuli. Cellular and secreted lipids were extracted with chloroform:methanol and separated by the thin layer chromatography (TLC), and [14C]labelled cholesterol and cholesteryl ester and [3H]labelled triglycerides and phospholipids were quantitated by the liquid scintillation counting. It demonstrated that ACTH administration did not result in any significant change in neither synthesis nor secretion of the studied lipids, this regardless of presence or absence of oleic acid, which is known to stabilize apoB and enhance apoB production. The present study suggests that ACTH lowers plasma lipids in humans mainly mediated by the inhibition of apoB synthesis and did not via the reduced lipid synthesis

Adrenocorticotrophic hormone lowers serum Lp(a) and LDL cholesterol concentrations in hemodialysis patients

Adrenocorticotrophic hormone lowers serum Lp(a) and LDL cholesterol concentrations in hemodialysis patients. Previously, we have shown that short-term administration of adrenocorticotrophic hormone (ACTH) results in reduced concentrations of apolipoprotein B-containing lipoproteins, including lipoprotein(a), and reduced activities of hepatic lipase. These effects were observed in steroid-treated patients suffering from iatrogenic ACTH deficiency and in healthy individuals. The direct nature of the influence of ACTH on hepatic lipoprotein metabolism was confirmed by in vitro experiments. The aim of the present investigation was to study the effects of ACTH treatment on uremic patients, who exhibit disturbed lipoprotein pattern due to the slow removal of triglyceride-rich lipoproteins and who probably are ACTH resistant. Eight patients on chronic hemodialysis were studied. After one intramuscular injection of Synacthen Depot (a synthetic ACTH1–24 preparation from Ciba Geigy AG, Basel, Switzerland) 1 mg, the only change noted was a significant reduction of 26% in median lipoprotein(a) concentration. After five injections, a further decrease (65%) was found in the lipoprotein(a) concentration. Also, reductions in median concentrations of total cholesterol, low density lipoprotein cholesterol and apolipoprotein B were observed. The magnitude of these changes was 15 to 30%. In contrast to previously studied groups, no changes were observed regarding triglyceride metabolism. Significantly increased median concentration of apolipoprotein CIII was found. However, the excess apolipoprotein CIII was confined to the fraction that was not associated with apolipoprotein B. Thus, administration of ACTH to uremic patients improved their atherogenic lipoprotein profile, a fact that may have future therapeutic implications. In comparison to previously studied groups, the uremic patients responded rather slowly and not at all regarding triglyceride metabolism

TO901317 regulating apolipoprotein M expression mediates via the farnesoid X receptor pathway in Caco-2 cells

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein M (apoM) may have potential antiatherosclerotic properties. It has been reported that apoM expression could be regulated by many intracellar and extracellar factors. In the present study we further investigated regulation of apoM expression in Caco-2 cells stimulated by a liver X receptor (LXR) agonist, TO901317.</p> <p>Materials and methods</p> <p>Caco-2 cells were cultured in the presence of either TO901317, farnesoid X receptor (FXR) antagonist guggulsterone or TO901317 together with guggulsterone at different concentrations for 24 hrs. The mRNA levels of ATP-binding cassette transporter A1 (ABCA1), apoA1, apoM, liver receptor homologue-1 (LRH-1) and short heterodimer partner 1 (SHP1) were determined by real-time RT-PCR.</p> <p>Results</p> <p>When Caco-2 cell cultured with TO901317 alone, the mRNA levels of ABCA1, apoA1, apoM, LRH-1 and SHP1 were significantly increased with dose-dependent manners (<it>p </it>< 0.05), whereas when the cells cultured with guggulsterone alone, the mRNA levels of apoM, SHP1 and LRH-1 (<it>p </it>< 0.05) were strongly inhibited. Moreover, guggulsterone could abolish the TO901317 enhanced mRNA levels of apoA1 apoM, SHP1 and LRH-1.</p> <p>Conclusion</p> <p>The present study demonstrated that LXR agonist TO901317 induced apoM expression in Caco-2 cells might be mediated via the LXR/FXR pathway.</p

Expression and localization of apolipoprotein M in human colorectal tissues

<p>Abstract</p> <p>Background</p> <p>It has been well documented that apolipoprotein M (apoM) is principally expressed in the liver and kidney. However we found that there was weak apoM expression in other tissues or organs too, which could not be ignored. In the present study, we therefore examined apoM expression in human colorectal tissues including cancer tissues, cancer adjacent normal tissues, polyp tissues and normal mucosa as well as inflammatory mucosa.</p> <p>Methods</p> <p>Tissue samples were collected from patients who underwent surgical resection or endoscopic examination. ApoM mRNA levels were determined by the real-time RT-PCR and apoM protein mass were examined by the immunohistochemistry.</p> <p>Results</p> <p>ApoM protein can be detected in all colorectal tissues. However, apoM protein mass were significantly lower in the cancer tissues than its matched adjacent normal tissues, polyp tissues, normal mucosa and inflammatory mucosa. In parallel, apoM mRNA levels in the colorectal cancer tissues (0.0536 ± 0.0131) were also significantly lower than those in their adjacent normal tissues (0.1907 ± 0.0563) (<it>P </it>= 0.033). Interestingly, apoM mRNA levels in colorectal cancer tissues were statistic significant higher in the patients with lymph node metastasis than the patients without lymph node metastasis (<it>P </it>= 0.008). Patients under Dukes' C and D stages had much higher apoM mRNA levels than patients under Dukes' A and B stages (<it>P </it>= 0.034).</p> <p>Conclusion</p> <p>It is concluded that apoM could also be expressed in human colorectal tissues besides liver and kidney. ApoM mRNA levels in the colorectal cancer tissues were significantly increased in the patients with lymph node metastasis. Whether increased apoM expression in the patients with lymph node metastasis being related to patients' prognosis and the physiopathological importance of apoM expression in colorectal tissues need further investigation.</p

Rosiglitazone Enhances Apolipoprotein M (Apom) Expression in Rat's Liver.

Apolipoprotein M (APOM) has been suggested as a vasculoprotective constituent of high density lipoprotein (HDL), which plays a crucial role behind the mechanism of HDL-mediated anti-atherosclerosis. Previous studies demonstrated that insulin resistance could associate with decreased APOM expressions. In agreement with our previous reports, here, we further confirmed that the insulin sensitivity was also reduced in rats treated with high concentrations of glucose; such effect could be reversed by administration of rosiglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ). The present study shows that Apom expression is significantly affected by either rosiglitazone or hyperglycemia alone without cross interaction with each other, which indicates that the pathway of Apom expression regulating by hyperglycemia might be differed from that by rosiglitazone. Further study indicated that hyperglycemia could significantly inhibit mRNA levels of Lxrb (P=0.0002), small heterodimer partner 1 (Shp1) (P<0.0001), liver receptor homologue-1 (Lrh1) (P=0.0012), ATP-binding cassette transporter 1 (Abca1) (P=0.0012) and Pparb/d (P=0.0043). Two-way ANOVA analysis demonstrated that the interactions between rosiglitazone and infusion of 25% glucose solution on Shp1 (P=0.0054) and Abca1 (4E, P=0.0004) mRNA expression was statistically significant. It is concluded that rosiglitazone could increase Apom expression, of which the detailed mechanism needs to be further investigated. The downregulation of Apom by hyperglycemia might be mainly through decreasing expression of Pparg and followed by inhibiting Lxrb in rats

Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPARβ/δ in HepG2 cells.

It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPARβ/δ pathway

Serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) in relation to markers of reproductive function in young males from the general Swedish population.

A time-related deterioration in male reproductive function caused by exposure to endocrine disrupters, including persistent organochlorines (POCs), has been hypothesized. In animal studies, POCs were found to have adverse effects on male reproductive function. However, little is known about the impact of POC exposure on reproductive parameters in men. In a study of 305 young Swedish men 18-21 years old from the general population, we correlated lipid-adjusted serum levels of 2,2',4,4',5,5' -hexachlorobiphenyl (CB-153)--an index substance for POC exposure--to markers of male reproductive function: testis size assessed by ultrasound, sperm concentration, total sperm count, sperm motility assessed manually and with a computer-aided sperm analyzer (CASA), and serum levels of follicle-stimulating hormone, inhibin B, testosterone, sexual hormone-binding globulin (SHBG), luteinizing hormone, and estradiol. We found weak but statistically significant, negative correlations between CB-153 levels and both the testosterone:SHBG ratio (r = -0.25, p < 0.001)--a measure of the biologically active free testosterone fraction--and CASA sperm motility (r = -0.13, p = 0.02). No statistically significant association with other seminal, hormonal, or clinical markers of male reproductive function was found. In previous studies of more highly POC-exposed groups of adult men, the correlation between POC exposure, including CB-153, and free testosterone levels was not statistically significant. The present study gives some tentative support for weak negative effects of CB-153 exposure on sperm motility and free testosterone levels in young men, but further semen studies on more highly exposed groups may give more firm conclusions on the hazard for male reproductive function from dietary POC exposure