Perceptual Quality of Nonesterified Fatty Acids Varies with Fatty Acid Chain Length.

Nonesterified fatty acids (NEFA) are effective taste stimuli. The quality they impart has not been well characterized. Sourness, and "fattiness" have been reported, but an irritation component has also been described and how these transition with gradations of aliphatic chain length has not been systematically studied. This study examined intensity and quality ratings of NEFA ranging from C2 to C18. Oral sites and the time course of sensations were also monitored. Given all NEFA contain carboxylic acid moieties capable of donating hydrogen ions, the primary stimulus for sour taste, testing was conducted with and without sour adaptation to explore the contribution of sour taste across the range of NEFA. Short-chain NEFA (C2-C6) were rated as predominantly sour, and this was diminished in C2 and C4 by sour adaptation. Medium-chain NEFA (C8-C12) were rated as mainly irritating with long-chain NEFA (C18) described mostly as bitter. The latter may reflect the lack of "fatty" lexicon to describe the sensation. Short-chain NEFA were mostly localized to the anterior tongue and were of rapid onset. The sensation from medium-chain NEFA was attributed to the lateral tongue, whereas medium- and long-chain NEFA sensations were predominantly localized to the back of the tongue and throat and had a longer lag time. The findings indicate there is a systematic transition of NEFA taste quality and irritation with increments in chain length and this is consistent with multiple modes of transduction.

Free Fatty Acids and Their Inflammatory Derivatives Affect BDNF in Stroke Patients.

OBJECTIVE: The neurotrophin brain-derived neurotrophic factor (BDNF) affects poststroke functional outcome, neurogenesis, neuroprotection, and neuroplasticity. Its level is related to the diet and nutritional status, and more specifically, it is free fatty acids (FFAs) and eicosanoids that can have an impact on the BDNF level. The aim of this study was to analyze the potential impact of FFAs and eicosanoids on the BDNF level in stroke patients. Material and Methods. Seventy-three ischemic stroke patients were prospectively enrolled in the study. Laboratory tests were performed in all subjects, including the levels of FFAs, eicosanoids, and BDNF. FFAs and inflammatory metabolites were determined by gas chromatography and liquid chromatography, while BDNF was evaluated by the immune-enzymatic method (ELISA). RESULTS: The plasma level of BDNF negatively correlated with C22:1n9 13 erucic acid, C18:3n3 linolenic acid (ALA), and lipoxin A4 15-epi-LxA4. A direct association was observed in relation to BDNF and C16:1 palmitoleic acid and C20:3n6 eicosatrienoic acid (dihomo-gamma-linolenic acid (DGLA)). CONCLUSIONS: Saturated fatty acids and omega-3 and omega-9 erucic acids can affect signaling in the BDNF synthesis resulting in the decrease in BDNF. There is a beneficial effect of DGLA on the BDNF level, while the effect of ALA on BDNF can be inhibitory. Specialized proresolving lipid mediators can play a role in the BDNF metabolism. BDNF can interact with inflammation as the risk factor in the cardiovascular disorders, including stroke.

Kupffer Cells Sense Free Fatty Acids and Regulate Hepatic Lipid Metabolism in High-Fat Diet and Inflammation.

A high fat Western-style diet leads to hepatic steatosis that can progress to steatohepatitis and ultimately cirrhosis or liver cancer. The mechanism that leads to the development of steatosis upon nutritional overload is complex and only partially understood. Using click chemistry-based metabolic tracing and microscopy, we study the interaction between Kupffer cells and hepatocytes ex vivo. In the early phase of steatosis, hepatocytes alone do not display significant deviations in fatty acid metabolism. However, in co-cultures or supernatant transfer experiments, we show that tumor necrosis factor (TNF) secretion by Kupffer cells is necessary and sufficient to induce steatosis in hepatocytes, independent of the challenge of hepatocytes with elevated fatty acid levels. We further show that free fatty acid (FFA) or lipopolysaccharide are both able to trigger release of TNF from Kupffer cells. We conclude that Kupffer cells act as the primary sensor for both FFA overload and bacterial lipopolysaccharide, integrate these signals and transmit the information to the hepatocyte via TNF secretion. Hepatocytes react by alteration in lipid metabolism prominently leading to the accumulation of triacylglycerols (TAGs) in lipid droplets, a hallmark of steatosis.

Impact of delipidated estrous sheep serum supplementation on in vitro maturation, cryotolerance and endoplasmic reticulum stress gene expression of sheep oocytes.

High lipid content of oocytes and embryos in domestic animals is one of the well-known factors associated with poor cryosurvival. Herein, we wanted to determine whether the use of delipidated estrous sheep serum during in vitro maturation (IVM) of ovine oocytes reduces the cytoplasmic lipid droplets content and improves embryo development and cryotolerance after vitrification. Cumulus oocytes complexes (COCs) were matured in vitro for 24 h in medium supplemented with whole or delipidated estrous sheep serum prior to vitrification. Neutral lipid present in lipid droplets of COCs, cleavage rate, embryo development rate on Day 6 and Day 8, and hatching rate on Day 8, were compared among experimental groups. Endoplasmic reticulum stress genes were evaluated in in vitro matured COCs under different lipid conditions prior to vitrification. The lipid droplets' content (mean fluorescence intensity) of oocytes cultured with IVM media supplemented with delipidated serum was lower than COCs matured with whole serum (7.6 ± 1.7 vs. 22.8 ± 5.0 arbitrary units, respectively; P< 0.05). Despite IVM treatment, oocytes subjected to vitrification showed impaired competence compared with the non-vitrified groups (P<0.05). No significant differences in embryo production were observed in non-vitrified COCs after maturation in delipidated or whole serum (33.4±4.9 vs 31.9 ±4.2). COCs matured in delipidated serum and subjected to vitrification showed increased expression of ATF4, ATF6, GRP78, and CHOP10 genes (ER stress markers). Collectively, our results demonstrate that although supplementation of IVM medium with delipidated estrous sheep serum reduces the presence of cytoplasmic lipid droplets in oocytes after maturation, oocyte cryotolerance is not improved. Notably, the expression of genes associated with the unfolded protein response (UPR) was increased in COCs, with fewer lipid droplets subjected to vitrification, suggesting that oocyte cryopreservation is associated with ER stress and activation of adaptive responses.

Free Fatty Acids: Circulating Contributors of Metabolic Syndrome.

Metabolic syndrome induces an increased cardiovascular morbidity and mortality. Most importantly, the prevalence of metabolic syndrome in adult population is expanding. Both clinical and preclinical studies indicate that increased Free Fatty Acids (FFAs) are involved in the pathogenesis of insulin resistance and subsequent development of metabolic syndrome. The relevance of FFAs in protecting and restoring tissue function is quite vast. The search to correlate the functional deterioration of the tissues within the cardiovascular system and increased plasma concentrations of FFAs has been reported. The importance of reduction in the consumption of dietary fatty acids along with the identification of dysregulated genes responsible for persistent increased FFAs uptake and mitochondrial ß-oxidation has been increasingly recognized. This review discusses the current empirical understanding of the different types of fatty acids and their metabolism and functions both in physiological and pathophysiological conditions. We also discuss in detail about the molecular and pathophysiological basis of increased FFAs, which augments Cardiovascular Disease (CVD).

The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines.

A dietary influence on cancer progression has been evident for many decades, and dietary fatty acids, particularly long chain mono- and polyunsaturated fatty acids, have been shown to play significant roles in influencing growth of a variety of human cancers. The discovery of the family of cell-surface free-fatty acid receptors, which include the long-chain fatty acid receptors FFA1 and FFA4, suggest that many of the effects of dietary fats could be receptor-mediated. FFA4 is ubiquitously expressed and has recently been shown to modulate a variety of important anti-inflammatory and metabolic processes. Since FFA4 is currently an attractive drug target for treatment of metabolic disorders such as diabetes and obesity, understanding its role in cancer progression is critical towards the drug discovery process. In this research update, the current body of knowledge on the role of this receptor in regulating cancer cell proliferation, migration, and invasion, as well as in vivo tumorigenesis is reviewed.

Effect of acute physiological free fatty acid elevation in the context of hyperinsulinemia on fiber type-specific IMCL accumulation.

It is well described that increasing free fatty acids (FFAs) to high physiological levels reduces insulin sensitivity. In sedentary humans, intramyocellular lipid (IMCL) is inversely related to insulin sensitivity. Since muscle fiber composition affects muscle metabolism, whether FFAs induce IMCL accumulation in a fiber type-specific manner remains unknown. We hypothesized that in the setting of acute FFA elevation by lipid infusion within the context of a hyperinsulinemic-euglycemic clamp, IMCL will preferentially accumulate in type 1 fibers. Normal-weight participants (n = 57, mean ± SE: age 24 ± 0.6 yr, BMI 22.2 ± 0.3 kg/m2) who were either endurance trained or sedentary by self-report were recruited from the University of Minnesota (n = 31, n = 15 trained) and University of Pittsburgh (n = 26, n = 14 trained). All participants underwent a hyperinsulinemic-euglycemic clamp in the context of a 6-h infusion of either lipid or glycerol control. A vastus lateralis muscle biopsy was obtained at baseline and end-infusion (6 h). The muscle biopsies were processed and analyzed at the University of Pittsburgh for fiber type-specific IMCL accumulation by Oil-Red-O staining. Regardless of training status, acute elevation of FFAs to high physiological levels (~400-600 meq/l) increased IMCL preferentially in type 1 fibers (+35 ± 11% compared with baseline, +29 ± 11% compared with glycerol control: P < 0.05). The increase in IMCL correlated with a decline in insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp (r = -0.32, P < 0.01) independent of training status. Regardless of training status, increase of FFAs to a physiological range within the context of hyperinsulinemia shows preferential IMCL accumulation in type 1 fibers.NEW & NOTEWORTHY This novel human study examined the effects of FFA elevation in the setting of hyperinsulinemia on accumulation of fat in specific types of muscle fibers. Within the context of the hyperinsulinemic-euglycemic clamp, we found that an increase of FFAs to a physiological range sufficient to reduce insulin sensitivity is associated with preferential IMCL accumulation in type 1 fibers.

El papel de los ácidos grasos libres en la resistencia a la insulina.

Free fatty acids are essential nutritional components and recent studies identified them as signaling molecules in various physiological processes. It has now been shown that high levels of free fatty acids, particularly saturated fatty acids, may be associated with insulin resistance in obese patients with type 2 diabetes mellitus. Insulin resistance is important in clinical since it is related to various diseases including type 2 diabetes mellitus, dyslipidemia, and abnormalities at cardiovascular level. Recent studies have proposed different molecular mechanisms by which these lipids may alter the signaling pathway of insulin. The purpose of this review is to highlight recent advances in the study of the effect of free fatty acids as modulators of insulin response.

Diabetic cardiomyopathy: a clinical entity or a cluster of molecular heart changes?

BACKGROUND: Although the increasing rate of cardiovascular mortality in patients with diabetes is thought to be due to the coronary atherosclerosis caused mainly by compounding factors such as dyslipidaemia and hypertension, it is now well documented that diabetes alone can lead to a vast array of molecular changes in the heart. DESIGN: The aim of this article was to comprehensively review the pathophysiological and molecular changes leading to diabetic cardiomyopathy (DCM), as well as to critically analyse the literature that offers evidence in favour and against the existence of the overt clinical expression of this entity. RESULTS: We included in the discussion studies that have revealed the existence of diabetic cardiomyopathy with unique remodelling pattern when compared to other types of cardiomyopathies. On the other hand, several studies debate the existence of clinically discernible cardiomyopathy caused only by diabetes and were also presented and discussed in details. CONCLUSION: Clinicians should be aware of DCM when facing patients with diabetes in order both to recognize on time relevant symptoms and to intensively look for and treat other compounding factors, apart from optimal glucose control. Furthermore, the elucidation of the pathophysiological mechanisms leading to DCM could provide new therapeutic targets for heart disease, which will be wonderful for the good of our patients.

WAX INDUCER1 (HvWIN1) transcription factor regulates free fatty acid biosynthetic genes to reinforce cuticle to resist Fusarium head blight in barley spikelets.

Fusarium head blight (FHB), caused by Fusarium graminearum, is one of the most devastating diseases of wheat and barley. Resistance to FHB is highly complex and quantitative in nature, and is most often classified as resistance to spikelet infection and resistance to spread of pathogen through the rachis. In the present study, a resistant (CI9831) and a susceptible (H106-371) two-row barley genotypes, with contrasting levels of spikelet resistance to FHB, pathogen or mock-inoculated, were profiled for metabolites based on liquid chromatography and high resolution mass spectrometry. The key resistance-related (RR) metabolites belonging to fatty acids, phenylpropanoids, flavonoids and terpenoid biosynthetic pathways were identified. The free fatty acids (FFAs) linoleic and palmitic acids were among the highest fold change RR induced (RRI) metabolites. These FFAs are deposited as cutin monomers and oligomers to reinforce the cuticle, which acts as a barrier to pathogen entry. Quantitative real-time PCR studies revealed higher expressions of KAS2, CYP86A2, CYP89A2, LACS2 and WAX INDUCER1 (HvWIN1) transcription factor in the pathogen-inoculated resistant genotype than in the susceptible genotype. Knockdown of HvWIN1 by virus-induced genes silencing (VIGS) in resistant genotype upon pathogen inoculation increased the disease severity and fungal biomass, and decreased the abundance of FFAs like linoleic and palmitic acids. Notably, the expression of CYP86A2, CYP89A2 and LAC2 genes was also suppressed, proving the link of HvWIN1 in regulating these genes in cuticle biosynthesis as a defense response.

Dietary Fatty Acids and Their Potential for Controlling Metabolic Diseases Through Activation of FFA4/GPR120.

It is well known that the amount and type of ingested fat impacts the development of obesity and metabolic diseases, but the potential for beneficial effects from fat has received less attention. It is becoming clear that the composition of the individual fatty acids in diet is important. Besides acting as precursors of potent signaling molecules, dietary fatty acids act directly on intracellular and cell surface receptors. The free fatty acid receptor 4 (FFA4, previously GPR120) is linked to the regulation of body weight, inflammation, and insulin resistance and represents a potential target for the treatment of metabolic disorders, including type 2 diabetes and obesity. In this review, we discuss the various types of dietary fatty acids, the link between FFA4 and metabolic diseases, the potential effects of the individual fatty acids on health, and the ability of fatty acids to activate FFA4. We also discuss the possibility of dietary schemes that implement activation of FFA4.

Role of adiponectin and free fatty acids on the association between abdominal visceral fat and insulin resistance.

BACKGROUND: Experimental studies have shown that high free fatty acid (FFA) and low adiponectin (ADIPO) levels are involved in the mechanisms by which adiposity promotes insulin resistance (IR). However, no previous clinical studies have simultaneously analysed the relative contribution of FFA and ADIPO levels on the relation of abdominal visceral fat (AVF) with insulin resistance. OBJECTIVE: To analyse the contribution of low ADIPO (adiponectin < =p25th: 8.67 µg/mL in women and 5.30 µg/mL in men), and high FFAs (FFAs > =p75th: 0.745 mEq/L in women and 0.60 mEq/L in men) to the association of high AVF (AVF > =p75th: 127 cm2 in women; 152.7 cm2 in men) with insulin resistance (HOMA-IR > =75th: 3.58 in women and 3.12 in men), in non-diabetic subjects. MATERIAL AND METHODS: A cross-sectional analysis was performed including 1217 control participants of the Genetics of Atherosclerotic Disease study (GEA). Clinical, tomographic and biochemical parameters were measured in all participants. Logistic regression models were used to assess the association of high AVF with IR stratifying according to gender, and to normal or low ADIPO and normal or high FFA serum levels. RESULTS: In comparison to referent group, in men low ADIPO unlike high FFA increased the risk of IR. Females with normal AVF and low ADIPO, or high AVF and normal ADIPO had aprox 3 folds risk of IR (OR [IC95%]: 3.7 [2.1-6.6], p < 0.001, and 3.4 [2.0-5.7], p < 0.001; respectively). The risk increased to 7.6 [4.2-13.8], p < 0.001 when high AVF and low ADIPO were present. Irrespective of AVF, the effect of low ADIPO on IR was higher than that seen for high FFA. Besides, our results suggest an additive effect of high AVF, high FFA and low ADIPO on the IR prevalence. CONCLUSIONS: The present study provides novel and important information about the combined effect of high AVF and low ADIPO on the risk of IR. Furthermore, our data suggest that the effect of low adiponectin levels on the high AVF-IR association is stronger than that observed for high FFA, suggesting that adiponectin could be used as biomarker to identify subjects at high risk for T2DM and CAD.

A novel antidiabetic therapy: free fatty acid receptors as potential drug target.

Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes (T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients, but also act as signaling molecules and stimulate key biological functions. Recent physiological and pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1-4, are receptors for FFAs. FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids (SCFAs). These FFA receptors (FFARs) mediate various physiological functions, depending on the carbon chain length of the FFAs and the ligand specificity of the FFARs. Functional analyses have revealed that FFARs mediate important metabolic functions, such as peptide hormone secretion and inflammation, and thereby contribute to energy homeostasis. Since imbalances in energy homeostasis lead to metabolic disorders, such as obesity and T2D, FFARs are considered to be key therapeutic targets in these diseases. In particular, recent studies have shown that the administration of selective agonists of FFAR1 and FFAR4 improved glucose metabolism and ameliorated systemic metabolic disorders. Furthermore, the biological functions of SCFAs in anti-inflammation and energy metabolism are linked with the activation of FFAR2 and FFAR3. Hence, in this review, we summarize the physiological functions of FFARs and discuss the potential of selective ligands of FFARs for development as drugs to treat metabolic disorders, such as T2D and obesity.

Fatty acids and the risk of death during acute myocardial ischaemia.

Plasma free fatty acids (non-esterified fatty acids) increase in the first hour of the onset of acute myocardial ischaemia. This results from catecholamine stimulation of adipose tissue lipolysis. It can lead to a metabolic crisis in the injured myocardium with the development of ventricular arrhythmias and increased early mortality. Preconditioning, ß-adrenergic blockade and glucose-insulin-potassium are possible therapeutic approaches, but anti-lipolytic agents, such as some nicotinic acid derivatives, can reduce plasma free fatty acid concentrations within minutes and have untried potential. A clinical trial of their effectiveness is needed from the first moment when a patient with an acute coronary syndrome is seen by paramedics.

Lipotoxic effect of p21 on free fatty acid-induced steatosis in L02 cells.

Nonalcoholic fatty liver disease (NAFLD) is increasingly regarded as a hepatic manifestation of metabolic syndrome. Though with high prevalence, the mechanism is poorly understood. This study aimed to investigate the effects of p21 on free fatty acid (FFA)-induced steatosis in L02 cells. We therefore analyzed the L02 cells with MG132 and siRNA treatment for different expression of p21 related to lipid accumulation and lipotoxicity. Cellular total lipid was stained by Oil Red O, while triglyceride content, cytotoxicity assays, lipid peroxidation markers and anti-oxidation levels were measured by enzymatic kits. Treatment with 1 mM FFA for 48 hr induced magnificent intracellular lipid accumulation and increased oxidative stress in p21 overload L02 cells compared to that in p21 knockdown L02 cells. By increasing oxidative stress and peroxidation, p21 accelerates FFA-induced lipotoxic effect in L02 cells and might provide information about potentially new targets for drug development and treatments of NAFLD.

Autonomic nerves and perivascular fat: interactive mechanisms.

The evidence describing the autonomic innervation of body fat is reviewed with a particular focus on the role of the sympathetic neurotransmitters. In compiling the evidence, a strong case emerges for the interaction between autonomic nerves and perivascular adipose tissue (PVAT). Adipocytes have been shown to express receptors for neurotransmitters released from nearby sympathetic varicosities such as adrenoceptors (ARs), purinoceptors and receptors for neuropeptide Y (NPY). Noradrenaline can modulate both lipolysis (via α2- and ß3-ARs) and lipogenesis (via α1- and ß3-ARs). ATP can inhibit lipolysis (via P1 purinoceptors) or stimulate lipolysis (via P2y purinoceptors). NPY, which can be produced by adipocytes and sympathetic nerves, inhibits lipolysis. Thus the sympathetic triad of transmitters can influence adipocyte free fatty acid (FFA) content. Substance P (SP) released from sensory nerves has also been shown to promote lipolysis. Therefore, we propose a mechanism whereby sympathetic neurotransmission can simultaneously activate smooth muscle cells in the tunica media to cause vasoconstriction and alter FFA content and release from adjacent adipocytes in PVAT. The released FFA can influence endothelial function. Adipocytes also release a range of vasoactive substances, both relaxing and contractile factors, including adiponectin and reactive oxygen species. The action of adipokines (such as adiponectin) and reactive oxygen species (ROS) on cells of the vascular adventitia and nerves has yet to be fully elucidated. We hypothesise a strong link between PVAT and autonomic fibres and suggest that this poorly understood relationship is extremely important for normal vascular function and warrants a detailed study.

FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture.

The accumulation of adipocytes in bone marrow is common in a variety of pathophysiological conditions, including obesity, insulin resistance, type 2 diabetes, and aging. Adipocytes in bone marrow exhibit severe adverse effect on osteoblast differentiation, proliferation, and function. However, the molecular mechanism of adipocytes lipotoxicity on osteoblasts is still far from completely understood. The present study was designed to investigate the signaling pathway responsible for adipocytes lipotoxicity on osteoblasts. Using a co-culture system, we have identified that free fatty acids (FFAs) released by the adipocytes inhibited osteoblasts proliferation and function and induced osteoblasts apoptosis, evidenced by decreased cell viability/proliferation, ALP activity, expression of runt-related transcription factor 2 (RunX2), type I collagen (ColA1) and osteocalcin and alizarin red staining. Dexamethasone (Dex) promoted the inhibitory effect of adipocytes on osteoblasts through stimulating FFAs release. Dex-exacerbated FFAs release from adipocytes contributes to reactive oxygen species (ROS) production. In the co-culture system, the phosphorylation of extracellular signal-regulated kinase (ERK)/P38 was increased and inhibition of ERK/P38 significantly suppressed adipocytes lipotoxicity. FFAs-generated ROS was responsible for adipocytes-induced activation of ERK/P38 signaling. In conclusion, FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture. The evidence provides new insights into the mechanisms underlying the lipotoxic effect of adipocytes on bone within the marrow microenvironment and prevention of lipotoxicity on bone metabolism.

[Effects of exercise and diet intervention on oxidative stress in insulin resistant rat].

OBJECTIVE: To investigate the effects of exercise, diet and their combination intervention on oxidative stress of insulin resistance rat. METHODS: Establish obesity-induced insulin resistance rat models. Obesity was assessed by the body weight and lipid ratio. Glucose tolerance was assessed by the integrated area under the curve for glucose (AUCg) during an oral glucose tolerance test (OGTT), then 8 weeks of exercise, diet, and combination interventions, respectively. To analyze serum free fatty acids (FFA) content, superoxide dismutase (SOD) and maleic dialdehyde (MDA) content in liver, adipose tissue and soleus muscle by biochemical method. Judge oxidative stressby FFA content and SOD/MDA. RESULTS: Three kinds of intervention reduced the body weight (P < 0.01), lipid ratio (P < 0.01) and AUCg (P < 0.01). Dietary and combination intervention lowered serum free fatty acid concentration (P < 0.01), separate exercise intervention had not such effect. Three kinds of intervention increased SOD/MDA in the liver and adipose tissue, exercise and combination intervention improved SOD/MDA in soleus muscle, dietary intervention alone had not the effect. CONCLUSION: Exercise and dietary intervention may improve the overall insulin resistance by alleviating oxidative stress.

Nutritional factors (nutritional aspects) in biliary disorders: bile acid and lipid metabolism in gallstone diseases and pancreaticobiliary maljunction.

Nutritional factors play a key role in the pathogenesis of biliary diseases such as gallstones and pancreaticobiliary maljunction. Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, the recent understanding of cholesterol gallstone pathogenesis is elaborated. On the other hand, there is another important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. Lysophosphatidylcholine (lysoPC), a derivative of phosphatidylcholine hydrolysis by phospholipase A2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. Increases in bile of lysoPC and phospholipase A2 have been reported in pancreaticobiliary maljunction and considered to be the major risk factor for biliary tract cancers. Further, oxidized fatty acids have been established as a potent ligand for G2A, a member of G protein-coupled receptor family that mediates a diverse array of biological processes including cell growth and apoptosis. Thus, both of lysoPC and free fatty acids are supposed to play an important role through G2A in biliary inflammation and carcinogenesis of pancreaticobiliary maljunction. Taken together, nutritional factors, especially lipid compounds, are seemingly crucial in the pathogenesis of biliary diseases, and such a causal relationship is reviewed by mainly authors' previous publications.

The dual role of free fatty acid signaling in inflammation and therapeutics.

Obesity, type 2 diabetes, insulin resistance, dyslipidemia, cardiovascular diseases and atherosclerosis have all been associated with high levels of free fatty acid (FFA). In the present review, we suggest that FFA may act as either pro- or anti-inflammatory agents depending on the chemical structure. Saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) significantly differ in their contributions to inflammation. While SFAs have been shown to induce inflammation, PUFAs have anti-inflammatory effects by downregulating NF-kappaB, IL-1ß, TNF-α and IL-6 despite upregulating of IL-10. It is suggested that FFA may activate Toll Like Receptor-4 (TLR4) and G protein-coupled receptors (GPCR) activating signaling pathways that promote production and release of inflammatory cytokines (IL-6 and TFN-α). Fatty acid action on TLR4, peroxisome proliferator-activated receptors (PPARs) and GPCRs are potential therapeutic targets for controlling FFA-induced inflammation. Approaches that downregulate the inflammatory properties of free fatty acid are discussed in this manuscript. In this review, some patents associated with controlling FFA effects are also reported.