lysophosphatidylethanolamine and Fatty-Liver

Plasma lysophospholipids have emerged as signaling molecules with important effects on inflammation, insulin resistance, and fatty liver disease, each of which is linked closely to obesity. Dietary n-3 (ω-3) polyunsaturated fatty acids (PUFAs) may be able to improve these conditions.. The objective of this study was to assess the response of plasma lysophospholipids to obesity, n-3 PUFA consumption, and a high-fat meal challenge to better understand the role of lysophospholipid metabolism in the progression of obesity-related disorders.. We determined the concentrations of 8 lysophosphatidylcholines, 11 lysophosphatidylethanolamines, and 7 lysophosphatidylinositols in the plasma of 34 normal-weight and 38 obese subjects randomly assigned to consume corn oil (control) or n-3 PUFA-rich fish oil (3 g/d; n = 15-19/group) for 90 d. Blood samples were collected on the last day of the study under fasting conditions and 6 h after a high-fat meal (1135 kcal, 86 g fat) challenge. The profile of secreted lysophospholipids was studied in HepG2 cells under palmitate-induced steatosis.. Obese and normal-weight subjects had different profiles of plasma lysophospholipids. A multivariate combination of the 26 lysophospholipids could discriminate between normal-weight and obese subjects with an accuracy of 98%. The high-fat meal challenge altered the concentration of plasma lysophosphatidylcholines in an oil treatment-dependent manner in normal-weight but not obese subjects, suggesting that obesity impairs the sensitivity of lysophospholipid metabolism to n-3 PUFAs. Noncytotoxic steatosis in HepG2 cells affected the secretion pattern of lysophospholipids, partially resembling the changes observed in the plasma of obese subjects.. Obesity has a substantial impact on lysophospholipid metabolism, altering the plasma lysophospholipid profile and abolishing its sensitivity to dietary n-3 PUFAs. These effects could contribute to the onset or progression of alterations associated with obesity, such as inflammation, insulin resistance, and fatty liver disease. This trial was registered at www.controlled-trials.com as ISRCTN96712688.

Topics: Adult; Diet, High-Fat; Dietary Fats; Fatty Acids, Omega-3; Fatty Liver; Female; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Lysophospholipids; Male; Middle Aged; Obesity

Whether bioactive lysophospholipids (lyso-PLs) and trimethylamine-N-oxide (TMAO) serve as non-invasive biomarkers in early human hypercholesterolemia (HC) is unknown. This study aimed to assess whether serum lyso-PLs and plasma TMAO may be suitable susceptibility/risk biomarkers of HC in humans. Secondarily, we aimed to evaluate the relationships between targeted metabolites, diet composition and circulating liver transaminases, and verify these results in hamsters.. A targeted metabolomics and lipidomics approach determined plasma TMAO and serum lysophosphatidylcholines (lyso-PCs) and lysophosphatidylethanolamines (lyso-PEs) in low (L-LDL-c) and moderate to high (MH-LDL-c) LDL-cholesterol subjects. Additionally, the relationships between targeted metabolites, liver transaminases and diet, particularly fatty acid intake, were tested. In parallel, plasma and liver lyso-PL profiles were studied in 16 hamsters fed a moderate high-fat (HFD) or low-fat (LFD) diet for 30 days.. Predictive models identified lyso-PC15:0 and lyso-PE18:2 as the most discriminant lyso-PLs among groups. In MH-LDL-c (n = 48), LDL-cholesterol and saturated FAs were positively associated with lyso-PC15:0, whereas in L-LDL-c (n = 70), LDL-cholesterol and polyunsaturated fatty acids (PUFAs) were negatively and positively related to lyso-PE18:2, respectively. Interestingly, in MH-LDL-c, the lower lyso-PE 18:2 concentrations were indicative of higher LDL-cholesterol levels. Intrahepatic accumulation of lyso-PLs-containing essential n-6 PUFAs, including lyso-PE18:2, were higher in HFD-fed hamsters than LFD-fed hamsters.. Overall, results revealed a possible hepatic adaptive mechanism to counteract diet-induced steatosis in animal and hypercholesterolemia progression in humans. In particular, low serum lyso-PE18:2 suggests a suitable susceptibility/risk biomarker of HC in humans.

Topics: Animals; Biomarkers; Cholesterol, LDL; Cricetinae; Cross-Sectional Studies; Diet; Dietary Fats; Disease Progression; Disease Susceptibility; Eating; Fatty Liver; Humans; Hypercholesterolemia; Liver; Lysophospholipids; Metabolome; Methylamines; Risk Assessment

A decrease of hepatocellular phosphatidylcholine (PC) is associated with hepatic injury, e.g., in nonalcoholic steatohepatitis (NASH). Therefore, we evaluated the hepatoprotective effect of a PC-precursor lipid specifically targeted to the liver. We synthesized the bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which was designed to target PC to hepatocytes by way of bile-acid transport systems. We synthesized a fluorescently labeled analogue UDCA-6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl PE (UDCA-NBDPE) for uptake and metabolism studies. Unexpectedly, the majority of UDCA-NBDPE was still intact and not hydrolyzed efficiently in HepG2 cells. For targeting in vivo, NBD fluorescence from UDCA-NBDPE-injected mice was recovered in the liver the most, whereas injection of NBDPE alone resulted in an even distribution in liver, kidneys, and intestine. Cytoprotection by UDCA-LPE was tested in starvation and tumor necrosis factor alpha (TNF-alpha) apoptosis models using HepG2 cells. Only the intact UDCA-LPE was able to persistently stimulate growth after 36 to 120-hour starvation, and significantly inhibited TNF-alpha-induced apoptosis. In both models, LPC, LPE, UDCA, or UDCA added with LPE exhibited weak to no cytoprotection. UDCA-LPE stabilized mitochondrial membranes by lowering mitochondrial membrane potential. Western blot analyses of phosphorylated Akt and glycogen synthase kinase-3 (GSK-3)alpha/beta revealed that UDCA-LPE activated phosphatidyl inositol 3-kinase (PI3K)/Akt signaling pathways. The PI3K inhibitor LY294002 or Akt small interfering (si)RNA consistently inhibited the proproliferative effects of UDCA-LPE during starvation. The TNF-alpha death-receptor extrinsic pathway involves caspase 8 activation, which is inhibited by cellular FLICE-inhibitory protein (cFLIP); thus, cFLIP siRNA was employed in our studies. cFLIP siRNA was able to reverse the cytoprotective effects of UDCA-LPE during TNF-alpha-induced apoptosis, and UDCA-LPE concomitantly upregulated protein expression of cFLIP(L).. UDCA-LPE, which targeted the liver in vivo, elicited potent biological activities in vitro by stimulating hepatocyte growth and by inhibiting TNF-alpha-induced apoptosis. Thus, UDCA-LPE may be suitable for evaluation of treatment efficacy in NASH.

Topics: Animals; Bile Acids and Salts; Cells, Cultured; Fatty Liver; Hepatitis; Lysophospholipids; Mice; Phospholipids; Ursodeoxycholic Acid