Almudena Ortega

Effects of meals rich in either monounsaturated or saturated fat on lipid concentrations and on insulin secretion and action in subjects with high fasting triglyceride concentrations

BACKGROUND The nature of dietary fats and fasting concentrations of triglycerides affect postprandial hypertriglyceridemia and glucose homeostasis. OBJECTIVES The objectives were to examine the effects of meals enriched in monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) on postprandial lipid, glucose, and insulin concentrations and to examine the extent of β cell function and insulin sensitivity in subjects with high fasting triglyceride concentrations. DESIGN Fourteen men with fasting hypertriglyceridemia and normal glucose tolerance were given meals (≈10 kcal/kg body weight) containing MUFAs, SFAs, or no fat. Blood samples were collected at baseline and hourly over 8 h for analysis. RESULTS The high-fat meals significantly increased postprandial concentrations of triglycerides, nonesterified fatty acids, and insulin and postprandial indexes of β cell function. However, postprandial indexes of insulin sensitivity decreased significantly. These effects were significantly attenuated with MUFAs relative to SFAs. CONCLUSIONS MUFAs postprandially buffered β cell hyperactivity and insulin intolerance relative to SFAs in subjects with high fasting triglyceride concentrations. These data suggest that, in contrast with SFAs, MUFA-based strategies may provide cardiovascular benefits to persons at risk by limiting lipid and insulin excursions and may contribute to optimal glycemic control after meal challenges.

A high-fat meal promotes lipid-load and apolipoprotein B-48 receptor transcriptional activity in circulating monocytes

BACKGROUND The postprandial metabolism of dietary fats results in the production of apolipoprotein B-48 (apoB48)-containing triglyceride-rich lipoproteins (TRLs), which cause rapid receptor-mediated macrophage lipid engorgement via the apoB48 cell surface receptor (apoB48R). Monocytes circulate together with apoB48-containing TRLs in the postprandial bloodstream and may start accumulating lipids even before their migration to tissues and differentiation to macrophages. OBJECTIVE We sought to determine whether circulating monocytes are equipped with apoB48R and whether, in the postprandial state, circulating monocytes accumulate lipids and modulate apoB48R transcriptional activity after intake of a high-fat meal. DESIGN In a crossover design, we studied the effect of a high-fat meal on fasting and postprandial concentrations of triglycerides, free fatty acids, cholesterol, and insulin in 12 healthy men. TRLs and monocytes were freshly isolated at fasting, hourly until the postprandial peak, and at the late postprandial phase. TRLs were subjected to triglycerides, apoB48, and apolipoprotein B-100 analyses; and lipid accumulation and apoB48R mRNA expression levels were measured in monocytes. RESULTS Monocytes showed a time-dependent lipid accumulation in response to the high-fat meal, which was paralleled by an increase in apoB48R mRNA expression levels. These effects were coincident only with an increase in apoB48-containing TRLs in the postprandial phase and were also observed ex vivo in freshly isolated monocytes incubated with apoB48-containing TRLs. CONCLUSION In a setting of abundant plasma apoB48-containing TRLs, these findings highlight the role of dietary fat in inducing lipid accumulation and apoB48R gene transcription in circulating monocytes.

Triglyceride-Rich Lipoprotein Regulates APOB48 Receptor Gene Expression in Human THP-1 Monocytes and Macrophages

The postprandial metabolism of dietary fats implies that the production of TG-rich lipoproteins (TRL) contributes to the progression of plaque development. TRL and their remnants cause rapid receptor-mediated monocyte/macrophage lipid engorgement via the cell surface apoB48 receptor (apoB48R). However, the mechanistic basis for apoB48 receptor (APOB48R) regulation by postprandial TRL in monocytes and macrophages is not well established. In this study, we investigated the effects of postprandial TRL from healthy volunteers on the expression of APOB48R mRNA and lipid uptake in human THP-1 monocytes and THP-1-derived macrophages. The expression of APOB48R mRNA was upregulated in THP-1 monocytes, but downregulated in THP-1-derived macrophages when treated with postprandial TRL (P < 0.05), in a dose- and time-dependent manner. TG and free cholesterol were dramatically increased in THP-1-derived macrophages (140 and 50%, respectively; P < 0.05) and in THP-1 monocytes (160 and 95%, respectively; P < 0.05). This lipid accumulation was severely decreased (~50%; P < 0.05) in THP-1-derived macrophages by small interfering RNA (siRNA) targeting of APOB48R. Using PPAR and retinoid X receptor (RXR) agonists, antagonists, and siRNA, our data indicate that PPARα, PPARγ, and RXRα are involved in postprandial TRL-induced APOB48R transcriptional regulation. Co-incubation with acyl-CoA synthetase or acyl-CoA:cholesterol acyltransferase inhibitors potentiated the effects of postprandial TRL on the expression of APOB48R mRNA in THP-1 monocytes and THP-1-derived macrophages. Our findings collectively suggest that APOB48R represents a molecular target of postprandial TRL via PPAR-dependent pathways in human THP-1 monocytes and macrophages and advance a potentially important link between postprandial metabolism of dietary fats and atherogenesis.

p38 MAPK Protects Human Monocytes from Postprandial Triglyceride-Rich Lipoprotein-Induced Toxicity

Postprandial triglyceride (TG)-rich lipoproteins (TRLs) transport dietary fatty acids through the circulatory system to satisfy the energy and structural needs of the tissues. However, fatty acids are also able to modulate gene expression and/or induce cell death. We investigated the underlying mechanism by which postprandial TRLs of different fatty acid compositions can induce cell death in human monocytes. Three types of dietary fat [refined olive oil (ROO), high-palmitic sunflower oil (HPSO), and butter] with progressively increasing SFA:MUFA ratios (0.18, 0.41, and 2.08, respectively) were used as a source of postprandial TRLs (TRL-ROO, TRL-HPSO, and TRL-BUTTER) from healthy men. The monocytic cell line THP-1 was used as a model for this study. We demonstrated that postprandial TRLs increased intracellular lipid accumulation (31-106%), reactive oxygen species production (268-349%), DNA damage (133-1467%), poly(ADP-ribose) polymerase 1 (800-1710%) and caspase-3 (696-1244%) activities, and phosphorylation of c-Jun NH2-terminal kinase (JNK) (54 kDa, 141-288%) and p38 (24-92%). These effects were significantly greater with TRL-BUTTER, and TRL-ROO did not induce DNA damage, DNA fragmentation, or p38 phosphorylation. In addition, blockade of p38, but not of JNK, significantly decreased intracellular lipid accumulation and increased cell death in postprandial TRL-treated cells. These results suggest that in human monocytes, p38 is involved in survival signaling pathways that protect against the lipid-mediated cytotoxicity induced by postprandial TRLs that are abundant in saturated fatty acids.

Nutrigenomics and Atherosclerosis: The Postprandial and Long-Term Effects of Virgin Olive Oil Ingestion

Epidemiological studies over the past 50 years have revealed numerous risk factors for atherosclerosis. They can be grouped into factors with an important genetic component and environmental factors, particularly diet, which is one of the major, constant environmental factors to which our genes are expose through life. When a gene is activated, or expressed, functionally distinct proteins are produced which can initiate a host of cellular metabolic effects. Gene expression patterns produce a phenotype, which represents the physical characteristics of an organism (e.g., hair color), or the presence or absence of a disease. Nutrition scientists realize more and more that phenotypic treats (health status) are not necessarily produce by genes alone but also by the interaction of bioactive food components on the levels of DNA, RNA, protein and metabolites (Muller & Kersten, 2003). Nutritional genomics came into being at the beginning of the 1990s. There is some confusion about the delimitation of the concept, as often the terms of nutritional genomics, nutrigenetics, and nutrigenomics, are used as synonyms. Nutritional genomics refers to the joint study of nutrition and the genome including all the other omics derived from genomics: transcriptomics (mRNA), proteomics (proteins), and metabolomics (metabolites) (Fig. 1). The terms nutritional genomics would be equivalent to the wide-ranging term of gene-diet interaction. Within the wide framework of the concept of nutritional genomics, we can distinguish 2 subconcepts: nutrigenetics and nutrigenomics. Currently, there is a wide consensus on considering nutrigenetics as the discipline that studies the different phenotypic response to diet depending on the genotype of each individual. The term nutrigenomics is subject to a greater variability in its delimitation, but it seems that there is a certain consensus in considering nutrigenomics as the discipline which studies the molecular mechanisms explaining the different phenotypic responses to diet depending on the genotype, studying how the nutrients regulate gene expression, and how these changes are interrelated with proteomics and metabolomics (Corella & Ordovas, 2009). This interpretation of the nutrigenomics concept is the one that we shall use in this Chapter. Atherosclerosis is a complex, multifactorial disease associated with accumulation of lipids in lesions along blood vessels, leading to the occlusion of blood flow, with oxidative and

Beyond Dietary Fatty Acids as Energy Source: A Point of View for the Prevention and Management of Type 2 Diabetes

Dietary fatty acids have been traditionally viewed as substrates for the generation of highenergy molecules and as precursors for the biosynthesis of macromolecules. However, accumulating data from multiple lines of evidence suggest that dietary fatty acids are linked to the pathogenesis of type 2 diabetes, which involves abnormalities in both insulin secretion and action (Lopez et al., 2010). Dietary fatty acids are absorbed into epithelial cells of the small intestine, are assembled into nascent triglyceride-rich lipoproteins, enter the bloodstream, and are transported to peripheral tissues. Therefore, the main physiological — but sometimes pathological — contribution to plasma triglycerides and tissue fatty acids, in terms of both quantity and quality, occurs during the postprandial period (Miles & Nelson, 2007). Acute elevation in plasma triglycerides, which may produce local elevation of fatty acids in beta-cells, is related to the increase of glucose-induced insulin secretion (Lopez et al., 2008; Lopez et al., 2010). Adipose tissue serves as a triglyceride storage site and, when necessary, stored triglycerides in adipocytes can be hydrolyzed by their adipose triglyceride and hormone-sensitive lipases to release fatty acids into the bloodstream. Excessive rates of lipid turnover have been shown to precede the development of type 2 diabetes in subjects with a family history of type 2 diabetes and nondiabetic obese individuals (Cusi, 2009). Decreased insulin sensitivity in adipose tissue is characterized by the increase of lipolysis and plasma fatty acid levels despite hyperinsulinemia, and impaired suppression of plasma fatty acid levels by insulin. This elevation in the plasma fatty acids, if chronic, induces a decrease in hepatic and skeletal muscle insulin sensitivity and detrimental effects on beta-cell function, which has been referred to as lipotoxicity (Giacca et al., 2011). Here, we review studies in insulin-secreting cell lines, islet cells, animal models, and human beings that have informed our current understanding of the mechanistic links among dietary fatty acids, beta-cell function, and insulin sensitivity.

Oleic Acid: The Main Component of Olive Oil on Postprandial Metabolic Processes

Publisher Summary Evidence from epidemiological studies suggests that a higher proportion of monounsaturated fatty acids (MUFA), notably oleic acid, in the diet is linked with a reduction in the risk of coronary heart disease (CHD). To achieve this benefit, olive oil as a major source of oleic acid is to replace a similar amount of saturated fat and not increase the total number of daily calories. The biochemical bases of the ameliorative effect of oleic acid are thought to be modification of plasma lipid and lipoprotein concentrations, inhibition of coagulation, improvement of glucose homeostasis, and attenuation of inflammation and oxidative status in fasting conditions. More recently, a body of evidence has grown that supports the hypotheses that postprandial metabolism of dietary fats plays a causal role in the pathogenesis and progression of CHD. However, the relevance of oleic acid regarding saturated fatty acids (SFA), notably palmitic acid, in dietary fats to influence postprandial metabolic processes is only partially understood. The proportion of oleic acid and palmitic acid in olive oil, compared to other dietary fats, could provide benefits and be considered as a nutritional determinant, at least, for regulation of coagulation and glucose homeostasis during the postprandial state.