Acute decrease in the stiffness of resting muscle belly due to static stretching.

The purpose of the study was to examine the acute effect of static stretching exercise on the resting stiffness of gastrocnemius muscle belly. Ten healthy young adults performed standing wall stretching in dorsiflexion for 1 min at a time and repeated five times. Before and after stretching, the shear modulus was measured in medial and lateral heads of the resting gastrocnemius muscle with ultrasound shear-wave elastography. After the stretching, dorsiflexion range of motion (ROM) of the ankle joint increased (P < 0.01) by 3.9° and returned in 20 min. Immediately after stretching, shear modulus decreased (P < 0.01) by 14%, compared with before stretching across muscle heads. The decrease in shear modulus returned in 20 min after stretching. In the comparison group of 10 additional subjects, the standing intervention without stretching had no influence on these measures. There was a negative correlation between dorsiflexion ROM and shear modulus in either head before and after stretching. The results demonstrate the transient decreases in the stiffness of the resting gastrocnemius muscle belly and indicate that joint flexibility is greater in individuals with lower resting stiffness of the muscle belly.

Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart.

Increased coronary blood vessel development could potentially benefit patients with ischemic heart disease. In a model of stress-induced myocardial ischemia, intracoronary injection of a recombinant adenovirus expressing human fibroblast growth factor-5 (FGF-5) resulted in messenger RNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved, effects that persisted for 12 weeks. Improved blood flow and function were associated with evidence of angiogenesis. This report documents, for the first time, successful amelioration of abnormalities in myocardial blood flow and function following in vivo gene transfer.

Range of motion exercise of temporo-mandibular joint with hot pack increases occlusal force in patients with Duchenne muscular dystrophy.

The purpose of this study is to evaluate whether the range of motion exercise of the temporo-mandibular joint (jaw ROM exercise) with a hot pack and massage of the masseter muscle improve biting disorder in Duchenne muscular dystrophy (DMD). The subjects were 18 DMD patients (21.3+/- 4.1 years old). The jaw ROM exercise consisted of therapist-assisted training (2 times a week) and self-training (before each meal every day). The therapist-assisted training consisted of the application of a hot pack on the cheek of the masseter muscle region (15 minutes), the massage of the masseter (10 minutes), and jaw ROM exercise (5 minutes). The self-training involved jaw ROM exercise by opening the mouth to the maximum degree, ten times. These trainings continued for six months. Outcomes were evaluated by measuring the greatest occlusal force and the distance at the maximum degree of mouth opening between an incisor of the top and that of the bottom. Six months later, the greatest occlusal force had increased significantly compared with that at the start of jaw ROM exercise (intermediate values: from 73.8N to 97.3N) (p = 0.005) as determined by the Friedman test and Scheffi's nonparametric test. The patients' satisfaction with meals increased. However, the maximum degree of mouth opening did not change after six months of jaw ROM exercise. Jaw ROM exercise in DMD is effective for increasing the greatest occlusal force.

Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects.

To clarify the physiological roles of CD36 as an oxidized low density lipoprotein (OxLDL) receptor, we analyzed the monocyte-derived macrophages from normal and two CD36-deficient subjects, since we identified the molecular abnormalities (Kashiwagi, H., Y. Tomiyama, Y. Kosugi, M. Shiraga, R. H. Lipsky, Y. Kanayama, Y. Kurata, and Y. Matsuzawa 1994. Blood. 83:3545-3552; and Kashiwagi, H., Y. Tomiyama, S. Honda, S. Kosugi, M. Shiraga, N. Nagao, S. Sekiguchi, Y. Kanayama, Y. Kurata, and Y. Matsuzawa. 1995. J. Clin. Invest. 95:1040-1046). Scatchard analysis of 125I-OxLDL binding showed a linear plot and the maximum binding was lower by approximately 40% in the macrophages from subjects with CD36 deficiency than those from normal controls. Competition studies showed that the uptake of 125I-OxLDL was suppressed by OKM5, an antibody against CD36, by 53% in normal control macrophages, but not in the CD36-deficient macrophages. After incubation with OxLDL for 24 h, cholesteryl ester mass accumulation was reduced by approximately 40% in the macrophages from CD36-deficient subjects than those from normal controls. These results suggest that CD36 is one of the physiological receptors for OxLDL. Since specific binding of OxLDL was only reduced by approximately 40% in spite of the complete deficiency of CD36, several other receptors also may have some role in OxLDL uptake. Further studies will be needed to assess the quantitative role of CD36 in foam cell formation in vivo.

Recurrent multinodular neurilemmoma of the female upper lip.

Neurilemmoma is the most commonly encountered nerve sheath tumour of the oral cavity. It generally appears as a single encapsulated nodule. The tongue is involved most frequently and the lip rarely. The tumour is usually uninodular. Multinodular neurilemmoma of the upper lip is very rare and has been reported in only one patient. This is the first reported case of multinodular neurilemmoma in the upper lip of a female.

Dietary fish, n-3 polyunsaturated fatty acid consumption, and depression risk in Japan: a population-based prospective cohort study.

Systematic review of observational studies has revealed that fish consumption and levels of n-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid are associated with a reduced risk of depression. A reverse J-shaped effect of n-3 PUFAs was suggested. However, there is limited evidence from populations with high fish consumption and no studies have used a standard psychiatrist-based diagnosis of major depressive disorder (MDD). Therefore, this population-based, prospective study investigated the association of dietary fish, n-3 PUFA, and n-6 PUFA consumption with risk of psychiatrist-diagnosed MDD in Japan. A total of 12 219 subjects were enrolled from the Saku area in 1990. Of these, we extracted 1181 participants aged 63-82 years who completed food frequency questionnaires in both 1995 and 2000 and also underwent a mental health examination in 2014-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for MDD according to fish intake and PUFA quartiles were calculated. Current MDD was diagnosed in 95 patients. We found a reduced risk of MDD in the third quartile for fish intake (111.1 g per day, OR=0.44, 95% CI=0.23-0.84), second quartile for EPA (307.7 mg per day, OR=0.54, 95% CI=0.30-0.99) and third quartile for docosapentaenoic acid (DPA) (123.1 mg per day, OR=0.42, 95% CI=0.22-0.85). ORs adjusted for cancer, stroke, myocardial infarction and diabetes remained significant for fish and DPA intake. Our results suggest that moderate fish intake could be recommended for the prevention of MDD in aged Japanese individuals.

Natural killer-like T-cell lymphoma in a calf.

A case of natural killer (NK)-like T-cell lymphoma in a 9-month-old female Holstein calf is described. The liver, spleen and lymph nodes were affected with lymphoma. The neoplastic cells showed not only epitheliotropism in the biliary epithelium and hepatic cords but also preferential homing to follicular centres of the lymph nodes. In the cytoplasm, there were eosinophilic granules of various sizes, which were positive with phosphotungstic acid haematoxylin and naphthol AS-D chloroacetate esterase. Erythrophagia by lymphoma cells was rarely detected. Immunohistochemically, the neoplastic cells expressed surface CD3, surface CD5 and CD57, and perforin expression was present in the cytoplasmic granules. The lymphoma described resembled feline NK-like T-cell lymphoma in epitheliotropism in the liver and phagocytic activity but differed in respect of follicular involvement and marked variation in granule size.

The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors.

Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.

Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death.

Exposure of mammalian cells to ultraviolet light, nutrient deprived culture media, hypoxia, environmental toxicants such as methyl mercury, methyl methanesulfonate, crocodilite asbestos or the agents that disrupt the function of endoplasmic reticulum (ER) leads to activation of the pro-apoptotic transcription factor GADD153/CHOP. Paradoxically, several of these agents also induce the anti-apoptotic transcription factor NF-kappaB. In this report, we demonstrate that NF-kappaB inhibits GADD153 activation in breast cancer cells exposed to nutrient deprived media, tunicamycin (which blocks protein folding in ER) or calcium ionopore (which depletes calcium stores in ER). Basal and calcium ionopore-induced GADD153 expression was more pronounced in fibroblasts obtained from mouse embryos lacking in p65 subunit of NF-kappaB compared to fibroblasts from wild type littermate embryos. Moreover, p65-/- fibroblasts were killed more efficiently by calcium ionopore and tunicamycin but not hydrogen peroxide compared to wild type fibroblasts. We also show that parthenolide, a NF-kappaB inhibitor, sensitizes breast cancer cells to tunicamycin. Transient transfection assay revealed that the p65 subunit but not the p50 subunit of NF-kappaB represses GADD153 promoter activity. These results establish a correlation between repression of pro-apoptotic genes by NF-kappaB and increased cell survival during ER stress as well as identify a distinct NF-kappaB regulated cell survival pathway.

Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169

Inhibition of DNA synthesis by griseolutein in Escherichia coli through a possible interaction at the cell surface.

Griseolutein acts as a bactericidal agent, its toxicity decreasing with increase in cell density. There is no evidence that griseolutein acts at a specific stage of cell cycle. Inhibition of incorporation of radioactive thymidine into acid-insoluble fraction of cells is marked and rapid, while inhibition of incorporation of uridine also takes place. Incorporation of 32Pi into the acid-insoluble fraction of cells is inhibited while the incorporation into the nucleotide pool is not. Concentration of any of the four deoxyribonucleoside triphosphates in griseolutein-treated cells are similar to or higher than those in untreated cells. No extensive degradation of cellualr DNA is caused by griseolutein. DNA synthesis in plasmolyzed cells in not inhibited by griseolutein.

Stimulation of the activity and mRNA level of hepatic triacylglycerol lipase by triiodothyronine in HepG2 cells.

We have studied the effects of triiodothyronine (T3) on the production of hepatic triacylglycerol lipase (HTGL) in the human hepatocellular carcinoma cell line, HepG2, by measuring its activity and mRNA levels. The HTGL activity released into the medium by heparin, increased after the addition of T3 in a both time- (27% increase after 24 and 75% increase after 48 h) and dose-dependent manner (maximum activity with over 0.2 micrograms/ml of T3 in the medium). Messenger RNA levels of HTGL in cells incubated with T3 for 24 and 48 h were increased by 33% and 98% compared to those of the control. These results suggest that the production of HTGL may be regulated by thyroid hormone at the level of gene expression.

Genetic analysis of a Japanese cerebrotendinous xanthomatosis family: identification of a novel mutation in the adrenodoxin binding region of the CYP 27 gene.

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive lipid-storage hereditary disorder, is caused by mutations in the sterol 27-hydroxylase gene (CYP 27). A 24-year-old female Japanese CTX patient and her parents were studied for a CYP 27 mutation. Multiple xanthomas were the main complaint of the patient and plasma cholestanol level was markedly elevated. Sterol analysis of a xanthoma biopsy confirmed cholesterol and cholestanol deposition, and the cholestanol accounted for 8.1% of the total sterols. Sterol 27-hydroxylase activity in fibroblasts derived from the patient was undetectable, while the activities in fibroblasts from her mother and father were 54% and 41% of the normal level, respectively. Direct sequence analysis showed a missense mutation of A for G substitution in the CYP 27 gene at codon 362 (CGT 362Arg to CAT 362His) with a homozygous pattern in the patient, and a heterozygous pattern in the parents. The mutation, which eliminates a normal HgaI endonuclease site at position 1195 of the cDNA and is located at the adrenodoxin binding region of the gene, is most probably responsible for the decreased sterol 27-hydroxylase activity in this Japanese CTX family. The combined data strongly support that the primary enzymatic defect in CTX is the disruption of sterol 27-hydroxylase and that the disease is inherited in an autosomal recessive trait.

Augmentation of granulocyte/macrophage colony-stimulating factor expression by ultraviolet irradiation is mediated by interleukin 1 in Pam 212 keratinocytes.

Keratinocytes are a potent source of a variety of cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, we have shown that ultraviolet B (UVB) irradiation augments GM-CSF mRNA expression by murine keratinocytes. This is reflected in the increased production of GM-CSF protein by these cells. In the same cell population, exposure to UVB irradiation increases interleukin 1 alpha (IL-1 alpha) mRNA and IL-1 protein as detected by bioactivity. This increase in IL-1 alpha precedes the increase of GM-CSF mRNA. Addition of recombinant IL-1 alpha to the medium increases GM-CSF mRNA expression. Anti-IL-1 alpha antibodies can completely inhibit UV-augmented GM-CSF mRNA expression. These results demonstrate that UVB irradiation-induced augmentation of GM-CSF is mediated by UV-induced IL-1 alpha.

Marked hypocholesterolemia in a case with adrenal adenoma--enhanced catabolism of low density lipoprotein (LDL) via the LDL receptors of tumor cells.

A 16-yr-old girl was hospitalized because of amenorrhea and virilism, and was diagnosed with an adrenal tumor on the right side. Her serum androgen levels were markedly elevated, and severe hypocholesterolemia (total cholesterol, 0.59 mmol/L) was observed. After resection of the tumor, her serum cholesterol level dramatically rose to normal, suggesting a role of this tumor in her marked hypocholesterolemia. To investigate the mechanism of hypocholesterolemia in this case, we examined the effects of dehydroepiandrosterone and dehydroepiandrosterone sulfate on the low density lipoprotein (LDL) receptor activity of fibroblasts. These hormones did not have any effect on LDL receptor activity. Northern blot analysis demonstrated that the LDL receptor messenger ribonucleic acid level of this tumor tissue was increased about 8-fold compared with that of normal adrenal cortex. The LDL receptor activity of the cultured cells established from this tumor was 2-fold higher than that of Hep G2 cells. Furthermore, the LDL receptor activity could not be down-regulated by an excessive dose of 25-hydroxycholesterol. These results suggest that increased LDL receptor activity and unrestricted uptake of LDL by the adrenal tumor may have caused the marked hypocholesterolemia in this patient.

Trigeminal mesencephalic neurons innervating functionally identified muscle spindles and involved in the monosynaptic stretch reflex of the lateral pterygoid muscle of the guinea pig.

Location of the neurons in the trigeminal mesencephalic nucleus innervating stretch receptors of the lateral pterygoid muscle and the mode of their synaptic connection on the lateral pterygoid motoneurons of the guinea pig were studied physiologically as well as morphologically, in comparison with the trigeminal mesencephalic neurons innervating muscle spindles in the superficial masseter muscle, with the following results: stimulation of the caudal half of the trigeminal mesencephalic nucleus evoked monosynaptic excitatory postsynaptic potentials in the ipsilateral lateral pterygoid motoneurons. Stimulation of the lateral pterygoid nerve directly evoked spike potentials in the neurons located in the caudal half of the ipsilateral trigeminal mesencephalic nucleus, which responded with increased firing to stretch, and with silent period to twitch, of the ipsilateral lateral pterygoid muscle. Averaging of intracellular potentials of the lateral pterygoid motoneurons with extracellular spike potentials of these trigeminal mesencephalic neurons revealed excitatory postsynaptic potentials after a monosynaptic latency, but no inhibitory postsynaptic potentials. Injection of horseradish peroxidase into the lateral pterygoid muscle labeled 15-20 cells in the caudal half of the ipsilateral trigeminal mesencephalic nucleus, while 174-228 cells retrogradely labeled by horseradish peroxidase were found throughout the whole rostrocaudal extent of the ipsilateral trigeminal mesencephalic nucleus following injection of horseradish peroxidase into the masseter muscle. It was concluded that neurons in the caudal half of the trigeminal mesencephalic nucleus send their peripheral processes to stretch receptors, presumably muscle spindles, in the ipsilateral lateral pterygoid muscle and that their central processes have excitatory synapses on ipsilateral lateral pterygoid motoneurons, thus comprising the afferent limb of a monosynaptic stretch reflex arc of the lateral pterygoid muscle of the guinea pig.

Postheparin lipolytic activity and plasma lipoprotein response to omega-3 polyunsaturated fatty acids in patients with primary hypertriglyceridemia.

The hypotriglyceridemic action of omega-3 (n-3) fatty acids is attributed primarily to reduction in hepatic triglyceride synthesis and reduced secretion of very-low-density lipoproteins (VLDLs). However, increased catabolism of triglyceride-rich lipoproteins was reported and could be due to increased availability of peripheral lipoprotein lipase (LPL) or hepatic lipase (HL). In this study plasma lipoproteins and postheparin activities of LPL and HL were determined in 12 patients with primary hypertriglyceridemia before and during isocaloric substitution of omega-3 fatty acids (10 g/d) for 4 wk. Omega-3 polyunsaturates resulted in 53% and 61% reductions in plasma triglyceride and VLDL-cholesterol concentrations, respectively (P less than 0.0001). However, low-density-lipoprotein (LDL)-cholesterol concentrations increased by 26% (P less than 0.001). Activities of postheparin LPL and HL essentially remained the same. Thus, in patients with primary hypertriglyceridemia, reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.

Influence of lovastatin on concentrations and composition of lipoprotein subfractions.

The effects of lovastatin therapy on concentrations and compositions of lipoproteins were examined in 14 patients with heterozygous familial hypercholesterolemia. The drug lowered plasma levels of cholesterol in total plasma, very low density + intermediate density lipoproteins (VLDL + IDL) and low density lipoproteins (LDL) by 25%, 41%, and 41%, respectively. Plasma total apo B was decreased by 35%. Three VLDL subfractions--VLDL-1, VLDL-2, and VLDL-3--of progressively higher density were examined. Lovastatin therapy reduced only the heaviest--VLDL-3. Concentrations of VLDL-1 and VLDL-2 were unchanged. Total VLDL-cholesterol/apo B was reduced significantly. Drug therapy also altered the composition of LDL as shown by decreasing the cholesterol/apo B. Finally, lovastatin significantly raised HDL-cholesterol concentrations. This study showed that lovastatin modifies the composition of the major apo B-containing lipoproteins as well as reducing their concentrations.

Localization of CD36 and scavenger receptor class A in human coronary arteries--a possible difference in the contribution of both receptors to plaque formation.

CD36 and scavenger receptor class A types I and II (SR-AI/II) are major receptors for oxidized low density lipoproteins (OxLDL) expressed on macrophages. To elucidate the role of these two macrophage scavenger receptors in the development of coronary atherosclerosis, we examined the localization of CD36 and SR-AI/II in human coronary atherosclerotic lesions. Serial cryostat sections of 49 coronary arteries obtained from 43 autopsied cases were examined immunohistochemically. Regarding the relationship between the severity of atherosclerosis and immunoreactivities to CD36, there was almost no immunoreactivity to CD36 in regions with diffuse intimal thickening, while the expression of CD36 was accelerated in parallel with the progression of atherosclerosis. In contrast, SR-AI/II was expressed persistently from regions with diffuse intimal thickening to atherosclerotic plaques. We also clarified the differential distribution of CD36 and SR-AI/II in atheromatous plaques. Close to the luminal surface of the intima, macrophages were relatively small in size, contained lesser lipids, and expressed SR-AI/II more abundantly than CD36. In contrast, macrophages in the core region were larger in size, contained more lipids, were strongly positive for CD36 and showed a weaker immunoreactivity to SR-AI/II than those in the luminal surface of the intima. In conclusion, the expression of CD36 and SR-AI/II on macrophages may be regulated differently in the process of coronary atherogenesis.

Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apo E Suita).

Apolipoprotein (apo) E7 was originally identified by Yamamura et al. in subjects with atherosclerotic cardiovascular diseases (J. Clin. Invest. 1984;74:1229). However, the lipoprotein abnormalities associated with apo E7 phenotype have not been elucidated. In the current study, to clarify the physiological roles of apo E7, lipoprotein abnormalities were studied in 12 apo E7 heterozygotes. A total of seven subjects were hyperlipidemic and five subjects were normolipidemic. The apo E phenotype was apo E7/3 in 11 subjects and apo E7/4 in one subject. Polymerase chain reaction revealed that all of the subjects with apo E7 phenotype had the same mutation as that of apo E(Suita) as reported previously (J. Biochem. 1989;105:249). All the hyperlipidemic subjects were over 40 years of age and two of them also had and severe coronary heart disease. Ultracentrifugal analysis revealed that the cholesterol level both in very low density lipoprotein and in intermediate density lipoprotein (IDL) was substantially higher in hyperlipidemic apo E7 heterozygotes, compared with control subjects and that the IDL cholesterol was also increased even in normolipidemic apo E7 heterozygotes. Polyacrylamide gel electrophoresis of lipoproteins showed a midband, which implies the increase of remnant lipoproteins, in 11 subjects out of 12, irrespective of the presence or absence of hyperlipoproteinemia. In two cases, a broad beta pattern was observed similar to that seen in type III hyperlipoproteinemia. Dietary therapy was dramatically effective for the treatment of hyperlipidemia in patients with apo E7. These findings confirm that apo E is crucial for remnant lipoprotein metabolism and that apo E7 is related to the increase in serum remnant lipoproteins, which leads to hyperlipoproteinemia in association with obesity, aging and impaired glucose metabolism.