Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme 5'AMP-activated protein kinase (AMPK) is activated by increases in intracellular AMP concentration through a complex interaction of phosphorylation and allosteric regulation. Actions of AMPK elucidated thus far suggest that AMPK may be a viable target for pharmacologic intervention in type II diabetes. Activation of AMPK is believed to mediate both the acute increase in skeletal muscle glucose uptake during exercise, as well as the adaptive responses to chronic exercise such as regulation of expression of components of the muscle glucose uptake system. In addition, AMPK is known to inhibit key enzymes involved in lipid and cholesterol synthesis, suggesting that activation of this kinase may also ameliorate dyslipidemia. To investigate the effects of AMPK activation in animal models of type II diabetes, db/db and ob/ob mice were administered 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR) subcutaneously either acutely (single injection) or twice per day for 8 days (chronic treatment). Blood glucose was lowered transiently in both db/db and ob/ob mice by acute AICAR treatment, returning to basal levels approximately 3 h after AICAR administration. In response to chronic treatment, blood glucose (measured 18 h post-AICAR administration) was significantly decreased in both mouse models when compared to vehicle control groups, with morning blood glucose values on Day 8 being decreased approximately 30-35% in both mouse models. Chronic AICAR administration also resulted in an elevation of total Glut4 concentration in skeletal muscle from ob/ob mice, but not db/db mice. In contrast to the beneficial effects on glucose metabolism, AICAR treatment of db/db and ob/ob mice led to approximately a 2.5-3-fold increase in serum triglyceride levels compared to vehicle-treated controls. These data suggest that pharmacological activation of AMPK may enhance glucose uptake in individuals with type II diabetes, however, this benefit may be offset by the concomitant elevation in triglycerides.
 ...
PMID:Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. 1206 77

Metabolic syndrome is a pathophysiological state in which risks for atherosclerosis are clustered. Etiology of metabolic syndrome is multi-factorial. Excess energy intake causes imbalance of energy transcription factors such as PPARs and SREBP-1c, which are deeply involved in lipid and carbohydrate metabolism, leading to insulin resistance and dyslipidemia. Especially hepatic SREBP-1c could be involved in production of remnant lipoproteins, fatty liver, and hepatic insulin resistance. Meanwhile, currently, therapeutic trend is activation of energy expenditure, in which PPAR alpha, delta, and AMP kinase are current targets of treatment. Proinflammatory agents should also be involved and adipocytokines could play an important role in peripheral insulin resistance.
 ...
PMID:[Pathophysiology of metabolic syndrome]. 1520 38

Free fatty acids (FFAs) play important physiological roles in many tissues as an energy source and as signaling molecules in various cellular processes. Elevated levels of circulating FFAs are associated with obesity, dyslipidemia, and diabetes. Here we show that GPR84, a previously orphan G protein-coupled receptor, functions as a receptor for medium-chain FFAs with carbon chain lengths of 9-14. Medium-chain FFAs elicit calcium mobilization, inhibit 3',5'-cyclic AMP production, and stimulate [35S]guanosine 5'-O-(3-thiotriphosphate) binding in a GPR84-dependent manner. The activation of GPR84 by medium-chain FFAs couples primarily to a pertussis toxin-sensitive G(i/o) pathway. In addition, we show that GPR84 is selectively expressed in leukocytes and markedly induced in monocytes/macrophages upon activation by lipopolysaccharide. Furthermore, we demonstrate that medium-chain FFAs amplify lipopolysaccharide-stimulated production of the proinflammatory cytokine interleukin-12 p40 through GPR84. Our results indicate a role for GPR84 in directly linking fatty acid metabolism to immunological regulation.
 ...
PMID:Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. 1696 19

Rat offspring prenatally exposed to alcohol display features of metabolic syndrome characterized by a low birth weight, catch-up growth, dyslipidemia, and insulin-resistant diabetes with increased gluconeogenesis, during adult life. Gluconeogenesis is partly regulated by cyclic AMP- and glucocorticoid-dependent mechanisms. Glucocorticoid action at the receptor level depends on its circulating concentrations and is amplified at the prereceptor level by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms. To determine whether 11beta-HSD1 is dysregulated in this rat model, we examined the expression and enzyme activity of 11beta-HSD1 and its regulator enzyme hexose-6-phosphate dehydrogenase (H6PD) in the liver of postnatal day 7 (neonatal) and 3-mo-old (adult) rat offspring prenatally exposed to alcohol. Measurements of 11beta-HSD1 and H6PD were also performed in the omental fat of adult rat offspring. In both neonatal and adult rats, prenatal alcohol exposure resulted in increased tissue corticosterone concentrations, increased expression, and oxoreductase activity of 11beta-HSD1, and a parallel increase of H6PD expression. The data suggest that due to both transcriptional and posttranscriptional dysregulations, rats exposed to alcohol early in life have increased 11beta-HSD1 activity, which may explain insulin-resistant diabetes in these animals later in life.
 ...
PMID:Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero. 1712 34

The biguanide metformin is an oral antihyperglycemic drug for the treatment of type 2 diabetes mellitus. Further, a moderate improvement of dyslipidemia by metformin was reported, and therefore, the effect of metformin on the release of apolipoprotein B (ApoB) and ApoE in primary human hepatocytes was determined. Metformin at 0.5 and 1 mM reduced hepatic ApoB secretion but ApoE was not altered. Metformin is well known to stimulate the AMP kinase that subsequently reduces hepatic nuclear factor 4-alpha (HNF4-alpha) and HNF4-alpha regulated genes like ApoB. However, HNF4-alpha was only diminished by 1 mM metformin and ApoB mRNA was not suppressed indicating that this pathway may not explain reduced ApoB release. Lower abundance of lysophosphatidylcholine (lysoPC) may also diminish ApoB secretion. Therefore, electrospray ionization tandem mass spectrometry was applied to measure cellular lipids. PC, lysoPC (produced by hydrolysis of PC), phosphatidylserine and sphingomyelin (derived from PC) were lower in metformin-treated hepatocytes whereas phosphatidylethanolamine, an alternative precursor of PC, was not affected. In addition, ABCB4, the canalicular membrane flippase essential for biliary PC secretion, was diminished. Supplementation with lysoPC led to a selective elevation of endogenous lysoPC and rescued ApoB secretion in metformin-treated cells. Therefore, it is concluded that metformin reduces lysoPC in human hepatocytes and this may secondarily lead to a therapeutically beneficial lower release of ApoB.
 ...
PMID:Metformin reduces cellular lysophosphatidylcholine and thereby may lower apolipoprotein B secretion in primary human hepatocytes. 1850 22

Obesity is a growing health problem in developed nations and in countries that are in the process of westernization like India. Obesity is linked with several health disorders such as hypertension and cardiovascular diseases, Type 2 diabetes, dyslipidemia and certain cancers. Currently, obesity-related malignancies, e.g., cancers of the breast, prostate and colon are the leading cancers in the industrialized societies. An increased amount of fat or adipose tissue in an overweight or obese person probably influences the development of cancer by releasing several hormone-like factors or adipokines. The majority of adipokines are pro-inflammatory, which promote pathological conditions like insulin resistance and cancer. On the other hand, many recent studies have shown that adiponectin, an anti-inflammatory adipokine, has anti-cancer and insulin-sensitizing effects. Adiponectin exerts its physiological functions chiefly by activation of AMP kinase via adiponectin receptors. Interestingly, several fruits and vegetables may contain adiponectin-like molecules or may increase the biosynthesis of adiponectin in our body. Studies on adiponectin analogues or adiponectin receptor agonists are a promising area of cancer chemoprevention research. In general, fruits and vegetables contain various dietary substances such as vitamins, minerals (like calcium and selenium), fiber and phytochemicals or phenolic compounds (like flavonoids and vanilloids), which may act as anti-cancer agents. Similarly, several dietary constituents including phytochemicals may have anti-obesity effects. Consumption of such dietary compounds along with caloric restriction and physical activity may be helpful in preventing obesity-related cancers. For this review article, we searched PubMed primarily to get the relevant literature.
 ...
PMID:Dietary factors and cancer chemoprevention: an overview of obesity-related malignancies. 1924 81

Extrarenal calcifications, particularly affecting the cardiovascular system, are common observations which can be a source of serious complications in patients with chronic renal disease, especially those on dialysis. In these patients, cardiovascular disease - myocardial infarction, arrhythmia, calcified valvulopathy, stroke, peripheral ischemic arteriopathy, calciphylaxy, etc. - is the leading cause of death (more than 50%). These complications are closely related to the presence of vascular calcifications (VC) which are much more frequent, severe, and progressive than in the general population. Previously, these calcifications were considered to arise via a passive process within the context of comorbid conditions without specific signs of gravity: high blood pressure, atherosclerosis, aging, diabetes, smoking, dyslipidemia, chronic micro-inflammation, hyperhomocysteinemia, disorders of calcium-phosphorus metabolism. It is now established that VC arise via a complex, probably regulated, active process analogous to the processes leading to bone formation and/or remodeling. New insight provided by a large body of work designed to ascertain the mechanisms underlying the onset of VC has enabled the development of new diagnostic and therapeutic approaches. It is now possible to identify factors clearly favoring the formation of VC: TNF-alpha (which stimulates cell necrosis/apoptosis), CRP, oxidized lipids, AGEs, leptin, inorganic phosphate, high calcium-phosphorus product (CaxPO(4)), calcium, 1,25-OH(2)D(3) and Vitamin D(3), PTHrP (via an intracrine pathway), cyclic AMP, TGF-beta, bone morphogenic protein 2 (BMP2) and factors protective against the formation of VC: magnesium, HDL, inorganic pyrophosphate, albumin, ahsg/fetuin A, osteopontin (OPN), osteoprotegerin (OPG), osteonectin (ON), bone morphogenic protein 7 (BMP7), klotho, PTHrP (via a paracrine pathway), matrix gla protein (MGP), PTH (via Msx2) and vitamin K. In conclusion, until recently, neglected disorders of calcium-phosphorus metabolism are currently recognized as the main actors in the process leading to vascular mediacalcosis in patients with chronic kidney failure.
 ...
PMID:[Origin of the mediacalcosis in kidney failure]. 1934 26

The metabolic syndrome, a cluster of conditions including abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure, is a natural consequence of over nutrition and a sedentary lifestyle. The prevalence of the metabolic syndrome has increased to epidemic proportions in the world. The exact pathogenesis of the metabolic syndrome remains unclear, but it is known to be a complex interaction between genetic, metabolic, and environmental factors. Promotion of physical activity and dietary management are still the main methods for the prevention and management of the metabolic syndrome. Numerous experimental and clinical studies have demonstrated the beneficial effects of high fiber diet on the metabolic syndrome. The principal beneficial effects of a fiber-rich diet in these patients are: prevention of obesity, improved glucose levels, and control of the profile of blood lipids. Dietary fiber may also favor the control of arterial blood pressure. How dietary fiber exerts its beneficial effects on the metabolic syndrome is not well understood. AMP activated protein kinase (AMPK) functions as a major cellular fuel gauge and a master regulator of metabolic homeostasis. Several lines of evidence suggest that AMPK can be activated by short-chain fatty acids (SCFA) either directly or indirectly. It is our hypothesis that the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome is the increased SCFA production in the colon leading to a higher concentration of SCFA in the portal vein, which activates the AMPK in the liver.
 ...
PMID:Activation of the AMP activated protein kinase by short-chain fatty acids is the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome. 1966 12

Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well-established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob;LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P < 0.01), triglycerides (P < 0.01), and free fatty acids (P < 0.001) in lean LDLR-/- mice, but not in ob/ob;LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob;LDLR-/- mice (P < 0.05) compared with olive oil fed ob/ob;LDLR-/- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P < 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob;LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice.
 ...
PMID:Dietary fish oil exerts hypolipidemic effects in lean and insulin sensitizing effects in obese LDLR-/- mice. 1986 3

Increased Very Low Density Lipoprotein (VLDL) production is a major feature of diabetic dyslipidemia with consequences on the metabolism of other lipoproteins such as Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL). More precisely, we observe, in patients with type 2 diabetes, an increased production of VLDL(1) particles that is potentially detrimental by generating atherogenic remnants, small dense LDL particles and triglyceride-rich HDL particles. Several pathophysiological factors are responsible for increased VLDL production, in type 2 diabetes. Among those, insulin resistance plays an important role. Indeed, defective activation of PI3-kinase, secondary to insulin resistance, is associated with a reduction of apoB degradation in the hepatocytes, a rise in MTP expression (by increasing nuclear transcription factors Fox01 and Foxa2) and an increased activity of phospholipase D1 and ARF-1, which are involved in VLDL(1) formation. Moreover, peripheral insulin resistance is responsible for increased lipolysis of adipose tissue leading to augmented portal flux of FFA to the liver and, as a consequence, activation of VLDL production. In addition, increased de novo lipogenesis is observed in type 2 diabetes. This is secondary to increased activation of SREBP-1c (Sterol Regulatory Element-Binding Protein-1c), mainly by Endoplasmic Reticulum stress, and of ChREBP (Carbohydrate Responsive Element Binding Protein), mainly by hyperglycemia. Furthermore, decreased plasma adiponectin observed in type 2 diabetes, may also play a role in increased VLDL production by decreasing liver AMP-kinase activation and by increasing plasma FFA levels as a consequence of reduced muscle FFA oxidation.
 ...
PMID:Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes. 2018 75


1 2 3 Next >>