Decreased adiponectin levels in familial combined hyperlipidemia patients contribute to the atherogenic lipid profile

Familial combined hyperlipidemia (FCH) is characterized by increased levels of total cholesterol, triglycerides, and/or apolipoprotein B. Other features of FCH are obesity and insulin resistance. Adiponectin is a secretory product of the adipose tissue. Low levels of adiponectin are associated with insulin resistance and accelerated atherosclerosis. The aim of this study was to determine whether decreased adiponectin levels are associated with FCH and its phenotypes. The study population comprised 644 subjects, including 158 patients with FCH. Serum adiponectin levels were determined using a commercially available ELISA. For both males and females, the mean adiponectin level (microg/ml) was significantly lower in FCH patients [2.0 (1.8-2.2) and 2.5 (2.3-2.8), respectively] compared with normolipidemic relatives [2.3 (2.2-2.5) and 3.1 (2.8-3.3), respectively] and spouses [2.4 (2.1-2.7) and 3.2 (2.8-3.6), respectively]. These differences remain significant after adjusting for waist circumference and insulin resistance. Low adiponectin level in FCH patients was a superior independent predictor of the atherogenic lipid profile, including high triglyceride levels, low HDL-cholesterol levels, and the amount of small, dense LDL present, compared with both obesity and insulin resistance. Low adiponectin levels may contribute to the atherogenic lipid profile in FCH, independent of insulin resistance and obesity, as measured by waist circumference. This finding implies a role of adipose tissue metabolism in the pathophysiology of FCH.     

Impact of adiponectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men

The aim of this study was first to examine the relationships between adiponectin gene (Apm1) polymorphisms and anthropometric indices as well as plasma adiponectin and lipoprotein/lipid levels, and then to investigate whether the presence of visceral obesity or insulin resistance may modulate the impact of these polymorphisms on metabolic risk variables. Molecular screening of the Apm1 gene was achieved, and a sample of 270 unrelated men recruited from the greater Quebec City area and selected to cover a wide range of body fatness values was genotyped. Sequencing of the Apm1 gene revealed two previously reported polymorphisms (c.45T>G and c.276G>T) as well as two newly identified genetic variations (-13752delT and -13702G>C). Carriers of the c.276T allele had higher LDL-cholesterol and lower HDL-triglyceride concentrations than did 276G/G homozygotes (P=0.02 and P=0.01, respectively). Carriers of the c.45G allele exhibited higher plasma adiponectin concentrations than did 45T/T homozygotes (P=0.04). After dividing each genotype group into subgroups for visceral AT, homozygotes for the normal allele at position -13752delT, carriers of the c.45G allele, and carriers of the c.276T allele had similar total apolipoprotein B (apoB) concentrations, whether they were viscerally obese or not. These results suggest that some Apm1 gene polymorphisms influence plasma adiponectin concentrations and lipoprotein/lipid levels. In addition, the impact of these polymorphisms is modulated by the presence of visceral obesity.     

Determinants of low HDL levels in familial combined hyperlipidemia

In familial combined hyperlipidemia (FCHL), affected family members frequently have reduced levels of HDL cholesterol, in addition to elevated levels of total cholesterol and/or triglycerides (TGs). In the present study, we focused on those determinants that are important regulators of HDL cholesterol levels in FCHL, and measured postheparin plasma activities of hepatic lipase (HL), lipoprotein lipase, cholesterol ester transfer protein, and phospholipid transfer protein (PLTP) in 228 subjects from 49 FCHL families. In affected family members (n = 88), the levels of HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, and apolipoprotein A-I were lower than in unaffected family members (n = 88) or spouses (n = 52). The main change was the reduction of HDL2 cholesterol by 25.4% in affected family members (P < 0.001 vs. unaffected family members; P = 0.003 vs. spouses). Affected family members had higher HL activity than unaffected family members (P = 0.001) or spouses (P = 0.013). PLTP activity was higher in affected than unaffected family members (P = 0.025). In univariate correlation analysis, a strong negative correlation was observed between HL activity and HDL2 cholesterol (r = -0.339, P < 0.001). Multivariate regression analysis demonstrated that gender, HL activity, TG, and body mass index have independent contributions to HDL2 cholesterol levels. We suggest that in FCHL, TG enrichment of HDL particles and enhanced HL activity lead to the reduction of HDL cholesterol and HDL2 cholesterol.     

Molecular mechanisms,prevalence, and molecular methods for familial combined hyperlipidemia disease: A review

Familial combined hyperlipidemia (FCHL) is the most common genetic dyslipidemia disorder which is accompanied by increasing of triglyceride and cholesterol. This disorder is a complex genetic disease although it also has monogenic forms. The familial form has several criteria for diagnosis that can be distinguished of nonfamilial position. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of FCHL. Environmental factors and the genetic background also play an important role in the FCHL pathogenesis. Many mechanisms and pathways are involved in lipid metabolism (ie, dysfunctional adipose tissue, hepatic fat and very low-density lipoprotein overproduction, triglyceride-rich lipoproteins, and clearance of low-density lipoprotein particles) that could lead to FCHL. Individuals with a positive family history like those who have a positive family history of cardiovascular diseases are more predispositions for this disorder. To date several methods have been used to identify the genetic background of the FCHL. In the current review, we summarized the prevalence and the molecular mechanisms involved in the FCHL disease. Moreover, we highlighted the used molecular methods for determining the genes involved in the FCHL.     

Visceral adiposity is associated with serum retinol binding protein-4 levels in healthy women

Objective: Retinol binding protein‐4 (RBP4) has been reported to impair insulin sensitivity throughout the body. We investigated the relationship between serum RBP4 levels and adiposity indices as well as metabolic risk variables. Research Methods and Procedure: We recruited a total of 102 healthy women 21 to 67 years old. We assessed body composition by computed tomography and divided the study population into four groups based on body weight and visceral fat area (non‐obese without visceral adiposity, non‐obese with visceral adiposity, obese without visceral adiposity, and obese with visceral adiposity). Serum RBP4 levels were measured by radioimmunoassay. Results: Despite similar levels of total body fat, non‐obese women had lower systolic blood pressure, total cholesterol, triglyceride (TG), low‐density lipoprotein (LDL)‐cholesterol levels, insulin resistance indices, and RBP4 levels than non‐obese women with visceral adiposity and had higher high‐density lipoprotein‐cholesterol levels. Similarly, obese women without visceral adiposity had lower blood pressure, total cholesterol, TG levels, insulin resistance indices, and RBP4 levels than obese women with visceral adiposity. In addition, despite having increased body fat, obese women without visceral adiposity had lower TGs, insulin resistance indices, and serum RBP4 levels than non‐obese women with visceral adiposity. By step‐wise multiple regression analysis, visceral fat areas and LDL‐cholesterol levels independently affected RBP4 levels. Discussion: We determined that serum RBP4 levels are independently associated with visceral fat and LDL‐cholesterol levels. These results suggest that, irrespective of body weight, visceral obesity is an independent predictor of serum RBP4 levels, and RBP4 may represent a link between visceral obesity and cardiovascular disease.     

A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is a common lipid disorder characterized by elevations of plasma cholesterol and/or triglyceride in first-degree relatives. A predominance of small, dense LDL particles and elevated apolipoprotein B (apoB) levels is commonly found in members of FCH families. Many studies have investigated the genetic mechanisms determining individuals' lipid levels, in FCH families. Previously, we demonstrated a major gene effect on LDL particle size and codominant Mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined FCH families. An elevation of apoB levels is associated metabolically with a predominance of small, dense LDL particles in FCH. To establish whether a common gene regulates both traits, we conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. In this study, we found that 66% of the total phenotypic correlation is due to shared genetic components. Further bivariate segregation analysis suggested that both traits share a common major gene plus individual polygenic components. This common major gene explains 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. Our study suggests that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCH in the families we studied.     

Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia

Plasma lipoprotein concentration, composition, and size were evaluated in two common familial forms of hypertriglyceridemia and compared with those in normal subjects. The very low density lipoproteins (VLDL) were triglyceride-enriched in familial hypertriglyceridemia (triglyceride/apoprotein B ratio: 25.7 +/- 8.9) as compared to normal (9.6 +/- 12.2, P < 0.001) or familial combined hyperlipidemia (9.7 +/- 3.3, P < 0.001). The diameter of VLDL was larger in familial hypertriglyceridemia (3.27 +/- 0.28 pm) than in familial combined hyperlipidemia (2.87 +/- 0.16 pm, P < 0.02). Although in familial hypertriglyceridemia VLDL tended to be larger, and in familial combined hyperlipidemia VLDL tended to be smaller than normal (3.08 +/- 0.48 pm), neither of these differences were significant. While VLDL was normally distributed in the control population, the size was skewed to larger particles in familial hypertriglyceridemia with fewer small particles (P < 0.05) and skewed to smaller particles in familial combined hyperlipidemia with fewer large particles (P < 0.05). VLDL was reciprocally related to low density lipoproteins (LDL) in familial combined hyperlipidemia (r = -0.80 to -0.87) suggesting that the concentrations of these individual lipoprotein groups were somehow interrelated. There was no significant relationship between these two lipoprotein classes in familial hypertriglyceridemia or in normals. In familial combined hyperlipidemia, the apoprotein A-I/A-II ratio was below normal (P < 0.01) suggestive of low HDL(2) levels. This change in apoprotein composition was independent of VLDL or LDL concentration. In familial hypertriglyceridemia, high density lipoprotein (HDL) cholesterol was reduced (33% below mean normal) and HDL triglyceride was increased (by 46%), while the concentration of apoA-I and apoA-II was normal. VLDL triglyceride was inversely related to HDL cholesterol in familial hypertriglyceridemia (r = -0.74, P < 0.005), but not in familial combined hyperlipidemia. The large, triglyceride-enriched VLDL observed in familial hypertriglyceridemia is compatible with the reported increase in VLDL triglyceride synthesis seen in this disorder. The increase in VLDL apoprotein B synthesis previously reported in familial combined hyperlipidemia was associated with VLDL of normal composition. The changes in HDL cholesterol in these two disorders might reflect exchange of triglyceride between VLDL and HDL or could be related to transfer of surface components during the catabolism of VLDL. The reciprocal relationship between various components of VLDL and LDL seen in familial combined hyperlipidemia, but not in familial hypertriglyceridemia or in normal subjects, might provide some insight into the pathological abnormalities in these disorders. The differences between these two common familial forms of hypertriglyceridemia provide further support that they are distinct entities.-Brunzell, J. D., J. J. Albers, A. Chait, S. M. Grundy, E. Groszek, and G. B. McDonald. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia.     

Postprandial variations of plasma inflammatory markers in abdominally obese men

Objective: Abdominal obesity is associated with a fasting proinflammatory condition. However, not much is known of the potential variations in circulating inflammatory markers after food intake. The purpose of the present study was to examine postprandial changes in plasma tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and C‐reactive protein (CRP) concentrations in men and their potential associations with fat distribution and metabolic profile variables. Research Methods and Procedures: Thirty‐eight men were given a high‐fat meal in the morning after an overnight fast, and TNF‐α, IL‐6, and CRP levels were measured in plasma at 0, 4, and 8 hours after the meal. Physical and metabolic profiles were also assessed for each participant. Results: We observed a substantial increase in circulating IL‐6 levels (p < 0.0001) after the meal. Although postprandial variations in circulating TNF‐α levels across time failed to reach statistical significance (p = 0.02), we noted a significant decrease in plasma TNF‐α concentrations 4 hours (?10%, p < 0.001 vs. 0 hours) after food intake. Plasma CRP levels were not affected by the fat load. We also noted that insulin‐sensitive individuals displayed a less pronounced inflammatory response after food intake than insulin‐resistant subjects. Discussion: Results of the present study show that consumption of a high‐fat meal leads to an increase in plasma IL‐6 concentrations and transient decrease in circulating TNF‐α levels in overweight men. Our results suggest a possible role of insulin resistance in the modulation of the postprandial inflammatory response, which could, in turn, contribute to worsen the state of insulin resistance.     

Iron deposits and dietary patterns in familial combined hyperlipidemia and familial hypertriglyceridemia

Iron deposits are associated with lipid phenotype in familial hypertriglyceridemias, mainly familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG). In turn, diet plays an important role in hypertriglyceridemias although it is not known if dietary patterns are associated with iron concentration in these disorders. The objective was to determine the relationship between diet and iron deposits, measured through serum ferritin concentration, in patients with FCH and FHTG. The study was composed of 140 patients, 107 with FCH and 33 with FHTG. Subjects completed a validated 137-item food frequency questionnaire. Dividing subjects by ferritin tertiles adjusted by sex, there were no significant differences in dietary patterns except in dairy products consumption which was lower in the highest ferritin tertile. Subjects were also divided by triglycerides tertiles adjusted by sex. Those subjects in the highest tertile had lower HDL cholesterol and higher ferritin concentrations. Regarding to dietary parameters, there were significant differences in marine omega three fatty acids and vegetables presenting higher and lower consumption, respectively, those patients in the highest tertile of triglycerides. Moreover, there was not a significant correlation between dietary iron intake and any parameter, both biochemical and dietary, including ferritin concentrations. In conclusion, in patients with primary hypertriglyceridemia, triglycerides are associated with ferritin concentrations but dietary patterns are not related to iron deposits. Our results highly support the concept that the genetic mechanisms driven to hypertriglyceridemia also favor iron overload.     

Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/- mice

Obesity is a life-threatening factor and is often associated with dysregulation of gene expression. Here, we show that the CNOT3 subunit of the CCR4-NOT deadenylase complex is critical to metabolic regulation. Cnot3(+/-) mice are lean with hepatic and adipose tissues containing reduced levels of lipids, and show increased metabolic rates and enhanced glucose tolerance. Cnot3(+/-) mice remain lean and sensitive to insulin even on a high-fat diet. Furthermore, introduction of Cnot3 haplodeficiency in ob/ob mice ameliorated the obese phenotype. Hepatic expression of most mRNAs is not altered in Cnot3(+/-) vis-à-vis wild-type mice. However, the levels of specific mRNAs, such as those coding for energy metabolism-related PDK4 and IGFBP1, are increased in Cnot3(+/-) hepatocytes, having poly(A) tails that are longer than those seen in control cells. We provide evidence that CNOT3 is involved in recruitment of the CCR4-NOT deadenylase to the 3' end of specific mRNAs. Finally, as CNOT3 levels in the liver and white adipose tissues decrease upon fasting, we propose that CNOT3 responds to feeding conditions to regulate deadenylation-specific mRNAs and energy metabolism.     

The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice

We examined mechanisms by which L-4F reduces obesity and diabetes in obese (ob) diabetic mice. We hypothesized that L-4F reduces adiposity via increased pAMPK, pAKT, HO-1, and increased insulin receptor phosphorylation in ob mice. Obese and lean mice were divided into five groups: lean, lean-L-4F-treated, ob, ob-L-4F-treated, and ob-L-4F-{"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002. Food intake, insulin, glucose adipocyte stem cells, pAMPK, pAKT, CB1, and insulin receptor phosphorylation were determined. Subcutaneous (SAT) and visceral adipose tissue (VAT) were determined by MRI and hepatic lipid content by magnetic resonance spectroscopy. SAT and VAT volumes decreased in ob-L-4F-treated animals compared with control. L-4F treatment decreased hepatic lipid content and increased the numbers of small adipocytes (P < 0.05) and phosphorylation of insulin receptors. L-4F decreased CB1 in SAT and VAT and increased pAKT and pAMPK in endothelium. L-4F-mediated improvement in endothelium was prevented by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002. Inhibition of pAKT and pAMPK by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 was associated with an increase in glucose levels. Upregulation of HO-1 by L-4F produced adipose remodeling and increased the number of small differentiated adipocytes. The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity.     

Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice

Caloric restriction, leanness and decreased activity of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fat-specific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. To determine the mechanisms by which a lack of insulin signaling in adipose tissue might exert this effect, we performed physiological and gene expression studies in FIRKO and control mice as they aged. At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, β-oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age. These changes in gene expression were correlated with increased cytochrome c and cytochrome c oxidase subunit IV at the protein level, increased citrate synthase activity, increased expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and PGC-1β, and an increase in mitochondrial DNA in WAT of FIRKO mice. Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.     

Postprandial triglyceride levels in familial combined hyperlipidemia. The role of apolipoprotein E and lipoprotein lipase polymorphisms

The effect of apolipoprotein E genotype and polymorphisms of lipoprotein lipase gene on plasma postprandial triglyceride levels in familial combined hyperlipidemic subjects and their relatives have not been sufficiently studied. This study included sixteen familial combined hyperlipidemic parents (G1): age: 52 +/- 9 years with total-cholesterol: 7.2 +/- 1.7 mmol/L, fasting triglycerides: 2.8 +/- 1.4 mmol/L and sixteen children (G2) (twelve were normolipidemic): of age: 22 +/- 5 years with total-cholesterol: 5.2 +/- 1.1 mmol/L, fasting triglycerides: 2.06 +/- 1.8 mmol/L and twelve normolipidemic, healthy controls. Blood samples were taken fasting and 2, 4, 6, 8, 10 hr postprandially after the standard fat rich test meal. We determined lipid parameters, apolipoprotein E and lipoprotein lipase HindIII and PvuII polymorphisms as well. The 6-hr critical postprandial triglyceride values were abnormal in both G1: 5.88 +/- 2.7 mmol/L and G2: 3.53 +/- 2.7 mmol/L (p <0.001), respectively, and differed significantly (p <0.001) from each other. The subjects of familial combined hyperlipidemic families with E4 allele in both generations exhibited significantly (p <0.001) higher and extended postprandial lipemia. We did not find significant effects of lipoprotein lipase HindIII or PvuII polymorphisms on the fasting lipid values alone, however in normolipidemic subjects from the same families the homozygosity of HindIII variation was associated with higher triglyceride postprandial peak (p <0.01). The main findings of our study are that i.) normolipidemic G2 subjects in familial combined hyperlipidemic families have already abnormal postprandial status, and ii.) the 6 h postprandial triglyceride values were correlated with fasting triglyceride levels, which showed association with the apolipoprotein E4 allele.     

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.     

Genome scan for quantitative trait loci influencing HDL levels: evidence for multilocus inheritance in familial combined hyperlipidemia

Several genome scans in search of high-density lipoprotein (HDL) quantitative trait loci (QTLs) have been performed. However, to date the actual identification of genes implicated in the regulation of common forms of HDL abnormalities remains unsuccessful. This may be due, in part, to the oligogenic and multivariate nature of HDL regulation, and potentially, pleiotropy affecting HDL and other lipid-related traits. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, we recently provided evidence of linkage of HDL level variation to the APOA1–C3–A4–A5 gene complex, in familial combined hyperlipidemia pedigrees, with an estimated number of two to three large QTLs remaining to be identified. We also presented results consistent with pleiotropy affecting HDL and triglycerides at the APOA1–C3–A4–A5 gene complex. Here we use the same MCMC analytic strategy, which allows for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. We now present results from a genome scan in search for the additional HDL QTLs in these pedigrees. We provide evidence of linkage for additional HDL QTLs on chromosomes 3p14 and 13q32, with results on chromosome 3 further supported by maximum parametric and variance component LOD scores of 3.0 and 2.6, respectively. Weaker evidence of linkage was also obtained for 7q32, 12q12, 14q31–32 and 16q23–24.     

Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells

Progressive renal disease is characterized by the accumulation of extracellular matrix proteins in the renal interstitium. Hence, developing agents that antagonize fibrogenic signals is a critical issue facing researchers. The present study investigated the blood-circulation-promoting Chinese herb, safflower, on fibrosis status in NRK-49F cells, a normal rat kidney interstitial fibroblast, to evaluate the underlying signal transduction mechanism of transforming growth factor-beta (TGF-beta), a potent fibrogenic growth factor. Safflower was characterized and extracted using water. Renal fibrosis model was established both in vitro with fibroblast cells treated with beta-hydroxybutyrate and in vivo using rats undergone unilateral ureteral obstruction (UUO). Western blotting was used to examine protein expression in TGF-beta-related signal proteins such as type I and type II TGF-beta receptor, Smads2/3, pSmad2/3, Smads4, and Smads7. ELISA was used to analyze bioactive TGF-beta1 and fibronectin levels in the culture media. Safflower extract (SE) significantly inhibited beta-HB-induced fibrosis in NRK cells concomitantly with dose-dependent inhibition of the type I TGF-beta1 receptor and its down-stream signals (i.e., Smad). Moreover, SE dose-dependently enhanced inhibitory Smad7. Thus, SE can suppress renal cellular fibrosis by inhibiting the TGF-beta autocrine loop. Moreover, remarkably lower levels of tissue collagen were noted in the nephron and serum TGF-beta1 of UUO rats receiving oral SE (0.15 g/3 ml/0.25 kg/day) compared with the untreated controls. Hence, SE is a potential inhibitor of renal fibrosis. We suggest that safflower is a novel renal fibrosis antagonist that functions by down-regulating TGF-beta signals.     

Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease

Dietary fatty acids are major contributors to the development and progression of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Dietary fatty acids also alter hepatic NKT cells that are activated by antigens presented by CD1d. In the current study, we examine the mechanism of dietary fatty acid induced hepatic NKT cell deficiency and its causal relationship to insulin resistance and NAFLD. We discover that dietary saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA), but not polyunsaturated fatty acids (PUFA), cause hepatic NKT cell depletion with increased apoptosis. Dietary SFA or MUFA also impair hepatocyte presentation of endogenous, but not exogenous, antigen to NKT cells, indicating alterations of the endogenous antigen processing or presenting pathway. In vitro treatment of normal hepatocytes with fatty acids also demonstrates impaired ability of CD1d to present endogenous antigen by dietary fatty acids. Furthermore, dietary SFA and MUFA activate the NFκB signaling pathway and lead to insulin resistance and hepatic steatosis. In conclusion, both dietary SFA and MUFA alter endogenous antigen presentation to hepatic NKT cells and contribute to NKT cell depletion, leading to further activation of inflammatory signaling, insulin resistance, and hepatic steatosis.     

Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: reduction during atorvastatin and fenofibrate therapy

Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism, is associated with an increased risk of atherosclerosis that is not fully explained by the metabolic disturbances of these patients. Oxidative damage to lipid components accumulating in the plasma of FCHL patients might contribute to explaining this lack of evidence. Cholesterol is one of the preferential targets of oxidation in LDL and this may contribute to setting a proatherogenetic phenotype in FCHL. We investigated plasma oxysterols (7-ketocholesterol and 7beta-hydroxycholesterol) and alpha-tocopherol as in vivo hallmarks of lipid-related oxidative stress. Oxidative stress hallmarks were measured in 45 FCHL patients and 54 sex- and age-matched healthy controls; in FCHL patients, oxidative stress and lipid profile parameters were also assessed in response to lipid-lowering drugs in a 24-week randomized, open-label trial with atorvastatin or fenofibrate. FCHL patients showed markedly increased levels of oxysterols (p < 0.001) and reduced alpha-tocopherol/total lipids (p < 0.001) compared to controls. These differences were independent of the presence of clinical atherosclerosis and persisted after correction for hyperlipidemia. Atorvastatin and fenofibrate significantly improved the lipid profile and caused a comparable decrease in plasma oxysterols, with the normalization of 7-ketocholesterol and a significant reduction of 7beta-hydroxycholesterol (p < 0.001). These drugs also decreased the ratio of alpha-tocopherol/total lipids by more than 30% (p < 0.001). In conclusion, FCHL patients showed increased hallmarks of cholesterol oxidation and decreased levels of alpha-tocopherol/total lipids. Atorvastatin and fenofibrate displayed comparable efficiency in decreasing oxysterols, but they further decreased lipid-corrected alpha-tocopherol levels in plasma. More research work is needed to understand the clinical meaning of these findings, which may help to understand the role of oxidative stress in FCHL and lipid-lowering therapy.