Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 9, Issue 1, 2009

The composition of dietary fat influences tissue fatty acid composition, which in turn impacts cellular function through a number of different processes. This includes changes in signaling, lipid metabolism, and transcriptional activities that normally function to maintain intracellular fatty acid homeostasis. The consumption of high levels of dietary fat in excess of caloric expenditure is linked with obesity and the disruption of normal homeostatic mechanisms governing lipid metabolism. Data from the Centers for Disease Control and Prevention show that obesity (defined as a BMI®30) represents a considerable health concern in the United States. Of particular note is that for adult men, the prevalence of obesity was 33% in 2006; the prevalence for adult women was slightly higher at 35%. Obesity is also of concern for children and adolescents where in 2006, 16% were considered obese (above the 95th percentile of the 2000 BMI-for-age growth charts). Statistics released by the American Heart Association show that the rise in obesity correlates with high low-density lipoproteincholesterol (LDL-C) levels. In 2004, nearly 33% of adults in the United States (age 20 and older) had LDL-C levels of 130 mg/dL or higher. Obesity is associated with disturbances in lipid metabolism including triglycerides, free fatty acids and lipoprotein cholesterol. One common finding in obese individuals is elevated levels of circulating free fatty acids that in turn increases fatty acid internalization and ectopic accumulation of triglycerides. Such disturbances in normal lipid metabolic homeostasis are associated with changes in fatty acid oxidation, accumulation of reactive oxygen species, the synthesis of ceramide and ER stress. The correlation between chronically elevated plasma free fatty acids and triglycerides and low highdensity lipoprotein-cholesterol (HDL-C) levels with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. This Special Issue of Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry, with a focus on dietary lipid absorption, is particularly timely given the obesity epidemic and comes from many of the leading experts in fatty acid and sterol transport. These review articles cover five general areas: [1] Fatty acid transport, with a focus on fatty acid translocase (CD36) and members of the fatty acid transport protein (FATP) family; [2] sterol transport, with a focus on Niemann-Pick C1-Like 1 (NPC1L1) and ATP binding cassette transporters G5 and G8 (ABCG5/ABCG8); [3] intracellular fatty acid trafficking, with a specific focus on liver fatty acid binding protein (L-FABP); [4] therapeutic properties of n-3 polyunsaturated fatty acids; and [5] chylomicron synthesis with a focus on regulation and the role of apolipoproteins.

The molecular mechanisms involved in intestinal absorption of dietary fatty acid are incompletely understood. Diffusion and protein mediated mechanisms appear to coexist although the role each component plays in the process remains to be defined. This review presents a summary of most recent evidence related to protein mediated fatty acid absorption by the small intestine. Our current understanding indicates that proximal versus distal intestinal segments play different roles in the absorptive process reflecting differential expression of transporters. Recent findings related to the fatty acid translocase CD36, which is most abundant proximally, support its role in coordinating proximal absorption of fatty acid and cholesterol for optimal chylomicron formation and secretion. Less supportive evidence is available related to other proteins implicated in intestinal fatty acid absorption. However, a brief overview is presented of recent work on the respective roles of intestinal SR-B1 and fatty acid transport protein 4 (FATP4). Intestinal fatty acid and cholesterol transporters represent potentially important and accessible targets for the management of hyperlipidemia by reducing absorption of dietary lipid. In the case of CD36, the relatively high frequency of polymorpshisms in the gene and the high incidence of CD36 deficiency in some populations suggest that it may contribute to individual variations in lipid absorption and processing. Its role in the absorption of both fatty acid and cholesterol make it a especially attractive drug target.

One principal process driving fatty acid transport is vectorial acylation, where fatty acids traverse the membrane concomitant with activation to CoA thioesters. Current evidence is consistent with the proposal that specific fatty acid transport (FATP) isoforms alone or in concert with specific long chain acyl CoA synthetase (Acsl) isoforms function to drive this energy-dependent process. Understanding the details of vectorial acylation is of particular importance as disturbances in lipid metabolism many times lead to elevated levels of circulating free fatty acids, which in turn increases fatty acid internalization and ectopic accumulation of triglycerides. This is associated with changes in fatty acid oxidation rates, accumulation of reactive oxygen species, the synthesis of ceramide and ER stress. The correlation between chronically elevated plasma free fatty acids and triglycerides with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. To this end, a detailed understanding of how fatty acids traverse the plasma membrane, become activated and trafficked into downstream metabolic pools and the precise roles provided by the different FATP and Acsl isoforms are especially important questions. We review our current understanding of vectorial acylation and the contributions by specific FATP and Acsl isoforms and the identification of small molecule inhibitors from high throughput screens that inhibit this process and thus provide new insights into the underlying mechanistic basis of this process.

Cholesterol is essential for the growth and function of all mammalian cells, but abnormally elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) are a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). For many years, statin drugs have been used to effectively lower LDL-C, but ASCVD still persists in most parts of the world. Hence, additional LDL-C lowering is now recommended, and the search for therapeutic strategies that work in synergy with statins has now begun. Intestinal absorption and biliary excretion of cholesterol represent two major pathways that continue to show promise as druggable processes. Importantly, both of these complex physiological pathways are tightly regulated by key proteins located at the apical surface of the small intestine and the liver. One of these proteins, the target of ezetimibe Niemann-Pick C1-Like 1 (NPC1L1), was recently identified to be essential for intestinal cholesterol absorption and protect against excessive biliary sterol loss. In direct opposition of NPC1L1, the heterodimer of ATP-binding cassette transporters G5 and G8 (ABCG5/ABCG8) has been shown to be critical for promoting biliary cholesterol secretion in the liver, and has also been proposed to play a direct role in intestinal disposal of sterols. The purpose of this review is to summarize the current state of knowledge regarding the function of these opposing apical cholesterol transporters, and provide a framework for future studies examining these proteins.

An epidemic of obesity, fueled in large part by increased consumption of diets enriched in saturated fat, has heightened interest in the pathways and mechanisms that modulate the uptake and utilization of individual dietary lipid components. Emerging evidence has implicated members of the intracellular fatty acid binding protein (FABP) multigene family as important metabolic sensors that may regulate substrate trafficking and metabolic compartmentalization. Among these, liver fatty acid binding protein (L-FABP, Fabp1) is an abundant cytosolic protein expressed in both mammalian small intestinal enterocytes and hepatocytes. L-Fabp-/- mice were protected against hepatic steatosis following a prolonged fast, suggesting a role in modulating hepatic FA trafficking in response to augmented lipid mobilization from adipose stores. In addition, L-Fabp-/- mice are protected against obesity and hepatic steatosis when fed a high saturated fat diet or a high saturated fat diet containing cholesterol (ie Western diet), but not when fed a high fat diet containing polyunsaturated fat. These findings imply substrate specificity in the lipid sensing functions of L-FABP. Together the data suggest that L-FABP regulates elements of both intestinal and hepatic FA trafficking as well as cholesterol metabolism and in turn exerts an important role in the pathogenesis of diet- induced obesity and hepatic steatosis through specific dietgene interactions.

Over the past several decades, data from both experimental animal studies and human clinical trials have shown that dietary n-3 polyunsaturated fatty acids (PUFA) exhibit anti-inflammatory bioactive properties, compared to n- 6 PUFA. Collectively, these studies have identified multiple mechanisms by which n-3 PUFA affect immune cell responses. In this review, we discuss the putative targets of anti-inflammatory n-3 PUFA, specifically, cytokine production, antagonism of n-6 PUFA metabolism, binding to nuclear receptors as ligands, and the alteration of signaling protein acylation. In addition, we investigate the effect of n-3 PUFA on the coalescence of lipid rafts, specialized signaling platforms in the plasma membrane.

With regard to inflammatory processes, the main fatty acids of interest are the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid, which is the precursor of inflammatory eicosanoids like prostaglandin E2 and leukotriene B4, and the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are found in oily fish and fish oils. EPA and DHA inhibit arachidonic acid metabolism to inflammatory eicosanoids. They also give rise to mediators that are less inflammatory than those produced from arachidonic acid or that are anti-inflammatory. In addition to modifying the lipid mediator profile, n-3 PUFAs exert effects on other aspects of inflammation like leukocyte chemotaxis, expression of adhesion molecules and production of inflammatory cytokines. Because of their potential as anti-inflammatory agents they may be of therapeutic use in a variety of acute and chronic inflammatory settings. Evidence of their clinical efficacy is reasonably strong in some settings (e.g. in rheumatoid arthritis) but is weak in others (e.g. in inflammatory bowel diseases and asthma). More, better designed and larger trials are required in inflammatory diseases to assess the therapeutic potential of long chain n-3 PUFAs in these conditions.

Dietary fat requires hydrolysis within the intestinal lumen prior to absorption. Once absorbed, the fatty acids (FA) and sn-2-monoacylglycerol (MAG) must be rapidly disposed of or the enterocytes risk membrane disruption. This is accomplished by their incorporation into the physico-chemically inert triacylglycerol (TAG). The TAG crosses the ER membrane and is incorporated into the developing chylomicron in a two-step process. In the first step, newly translated apolipoprotein B48 (apoB48) is chaperoned by the microsomal triglyceride transport protein (MTP) in the ER lumen where the apoB48 participates in the formation of the primordial, dense chylomicron consisting of apoB48, phospholipids, cholesterol and a small amount of TAG. This dense chylomicron then combines with a TAG, cholesterol ester rich lipid particle to form the pre-chylomicron within the ER lumen. The pre-chylomicron is then selected for inclusion in the prechylomicron transport vesicle (PCTV) that transports the pre-chylomicron to the cis Golgi. The PCTV budding step is rate limiting for this process. PCTV budding requires liver fatty acid transport protein (L-FABP) or cytosol and ATP. Vesicle associated membrane protein 7 (VAMP7) helps direct the vesicle to its cognate SNARE complex on the cis Golgi. rLFABP generated PCTV do not associate with the Golgi. The fused PCTV deliver the chylomicrons to the Golgi for additional processing prior to their transport in an unknown vesicle to the basolateral membrane for exocytosis and transport into the lymph. In vivo the amount of chylomicrons delivered to the mesenteric lymph for a given amount of dietary TAG can be proportionally regulated by the amount of phosphatidylcholine present in the intestinal lumen. In vitro PCTV generation may be regulated by the action of PKCζ.

Dietary lipids and many lipophilic vitamins and compounds are transported in lymph by chylomicrons which are secreted by the enterocytes of the small intestine. This article reviews our current understanding of the digestion, uptake, intracellular metabolism, and packaging of dietary lipids into chylomicrons. An overview of the digestive enzymes involved in the digestion of triacylglyerol is provided. We also discuss the relative importance of vesicles and micelles in delivering the lipid digestion products for uptake by the small intestine. While there is certainly evidence for the involvement of transporters in the uptake of cholesterol by enterocytes, we believe the uptake of fatty acids is predominantly passive. The active uptake of fatty acids is only important when the luminal fatty acid concentration is very low (probably to ensure that the essential fatty acids are not lost). We also describe the roles of the various lipid esterifying enzymes in the metabolism of the absorbed partial glycerides and fatty acids. In addition, the present review illustrates the mechanism by which intracellular assembly and modification occur during the formation of chylomicrons and very low density lipoprotein. Furthermore, clinical disorders related to intestinal lipid transport are discussed. The authors' basic and clinical insights into the processes of intestinal lipid absorption provide valuable information about effective, safe ways to prevent obesity and hyperlipidemia.

Due to an over sight on the part of the publishers, Bentham Science Publishers, there have been two misprints in Figs. (1 and 2) in the review article entitled “5-HT and NA reuptake inhibitors and Appetite Regulation: the role of the central 5-HT network.”, by Dr. Katsunori Nonogaki, Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry, December 2008, Vol. 8(4), pp. 303-310.