Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update.

Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different populations. About 10% of these patients suffer from cardiovascular disease and this number is increased by up to 11.3% in the young survivors of myocardial infarction and by 40% among all the survivors of myocardial infarction. Although initially thought to be that FCHL has an inheritance pattern of monogenic, the disease's etiology is still not fully understood and it appears that FCHL has a complex pattern related to genetic variants, environmental factors, and lifestyles. Two strategies have been used to identify its complex genetic background: candidate gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL with a variable degree of scientific evidence. Until now, more than 30 different genetic variants have been identified related to FCHL. In this study, we aimed to review the individual genes that have been described in FCHL and how these genes and variants can be related to the current concept of metabolic pathways resulting in familial combined hyperlipidemia.

Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies.

Among different types of dyslipidemia, familial combined hyperlipidemia (FCHL) is the most common genetic disorder, which is characterized by at least two different forms of lipid abnormalities: hypercholesterolemia and hypertriglyceridemia. FCHL is an important cause of cardiovascular diseases. FCHL is a heterogeneous condition linked with some metabolic defects that are closely associated with FCHL. These metabolic features include dysfunctional adipose tissue, delayed clearance of triglyceride-rich lipoproteins, overproduction of very low-density lipoprotein and hepatic lipids, and defect in the clearance of low-density lipoprotein particles. There are also some genes associated with FCHL such as those affecting the metabolism and clearance of plasma lipoprotein particles. Due to the high prevalence of FCHL especially in cardiovascular patients, targeted treatment is ideal but this necessitates identification of the genetic background of patients. This review describes the metabolic pathways and associated genes that are implicated in FCHL pathogenesis. We also review existing and novel treatment options for FCHL. © 2019 IUBMB Life, 71(9):1221-1229, 2019.

Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Dynamics of human adipose lipid turnover in health and metabolic disease.

Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.

Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia.

BACKGROUND: Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR). MATERIALS AND METHODS: A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione (GSSG), reduced glutathione (GSH) and TRX. RESULTS: Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR (P < 0·01). TRX levels correlated with higher insulin resistance. CONCLUSION: Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients.

Familial combined hyperlipidemia: from molecular insights to tailored therapy.

PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.

Positional cloning of the combined hyperlipidemia gene Hyplip1.

Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We fine-mapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO2 production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism.

Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice.

Upstream transcription factor 1 (USF1) has been associated with familial combined hyperlipidemia, the metabolic syndrome, and related conditions, but the mechanisms involved are unknown. In this study, we report validation of Usf1 as a causal gene of cholesterol homeostasis, insulin sensitivity and body composition in mouse models using several complementary approaches and identify associated pathways and gene expression network modules. Over-expression of human USF1 in both transgenic mice and mice with transient liver-specific over-expression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL/VLDL cholesterol and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic over-expression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2-centered module. In all three mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes.

A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.

We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans.

Linkage and association of phospholipid transfer protein activity to LASS4.

Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.

Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway.

OBJECTIVE: Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. METHODS AND RESULTS: Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P<0.001) and 51% (P<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR. CONCLUSIONS: Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.

Different impacts of cardiovascular risk factors on oxidative stress.

The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant enzyme genes (CuZn-SOD, CAT, GPX1, GSR, GSS and TXN) were measured in mononuclear cells of controls (n = 20) and patients (n = 90) by assessing mRNA levels. Activity of some of these antioxidant enzymes was also tested. An increase in OS and pro-oxidant gene mRNA values was observed in patients compared to controls. The hypertensive group showed not only the highest OS values, but also the highest pro-oxidant activation compared to those observed in the other groups. In addition, in HT a significantly reduced antioxidant activity and mRNA induction of antioxidant genes were found when compared to controls and the other groups. In FH and FCH, the activation of pro-oxidant enzymes was also higher and antioxidant ones lower than in the control group, although it did not reach the values obtained in hypertensives. The thioredoxin system was more activated in patients as compared to controls, and the highest levels were in hypertensives. The increased oxidative status in the presence of cardiovascular risk factors is a consequence of both the activation of pro-oxidant mechanisms and the reduction of the antioxidant ones. The altered response of the main cytoplasmic antioxidant systems largely contributes to OS despite the apparent attempt of the thioredoxin system to control it.

Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus.

PURPOSE OF REVIEW: Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach. RECENT FINDINGS: Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients. SUMMARY: Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy.

FABP4 plasma levels are increased in familial combined hyperlipidemia.

The lipid profile of familial combined hyperlipidemia (FCHL) shares some characteristics with atherogenic dyslipidemia seen in diabetes, metabolic syndrome, and obesity. Adipocyte fatty acid-binding protein 4 (FABP4) appears to be a determinant of atherogenic dyslipidemia. We examined relationships between FABP4 plasma concentrations, dyslipidemia, and metabolic variables in patients with FCHL. We studied 273 unrelated FCHL patients and 118 control subjects. FABP4 was higher in FCHL than controls, with mean levels of 21.8 (10.1) microg/l and 19.2 (9.2) microg/l, respectively (adjusted P= 0.012). In FCHL, FABP4 correlated to body mass index (BMI), waist circumference, insulin levels, and homeostasis model assessment (HOMA) index (all P< 0.05), but not to lipid levels, whereas in obese patients, FABP4 correlated to triglyceride levels (r = 0.303, P= 0.014) and very low density lipoprotein size (r = 0.502, P = 0.001), as determined by nuclear magnetic resonance. Associations of FABP4 with BMI and waist circumference, but not with insulin levels, persisted in this subgroup. Plasma FABP4 does not influence the lipid phenotype of FCHL. In a small subgroup of obese FCHL, FABP4 levels were associated with triglyceride-rich lipoproteins independent of insulin resistance. These results support a hyperlipidemic mechanism of FCHL different from similar metabolic conditions where fat mass is strongly related to FABP4 and hypertriglyceridemia.

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Xanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR). METHOD AND RESULTS: 40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity. CONCLUSIONS: Subjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.

Adiponectin multimer distribution in patients with familial combined hyperlipidemia.

Adiponectin is secreted from adipocytes in different multimers, of which the high molecular weight (HMW) form is supposed to mediate favorable metabolic and anti-atherogenic effects. We determined adiponectin multimers in 29 female and 22 male patients with familial combined hyperlipidemia (FCH) and 51 age-, gender-, and BMI-matched controls in relation to cardiovascular disease (CVD). We observed a clear sexual dimorphism of total adiponectin and its multimers. Female, but not male, FCH patients had significant lower total adiponectin and both HMW and low molecular weight (LMW) adiponectin than controls. The adiponectin sensitivity index (ASI), reflected by HMW/total adiponectin, and the LMW/HMW adiponectin ratio did not differ significantly between FCH females and control females. However, FCH females with CVD exhibited significantly lower ASI (34.2+/-10.1% vs 46.0+/-7.1%) and higher LMW/HMW ratio (1.5+/-0.8 vs 0.7+/-0.3) compared to FCH females without CVD, reflecting a more atherogenic adiponectin multimer distribution.

Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation.

OBJECTIVE: Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1beta, and that in vitro both PGC-1beta and PGC -1alpha increase PPARalpha-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPARalpha agonist Wy14,643 (Wy). METHODS AND RESULTS: C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1alpha or PGC-1beta. On chow, hepatic PGC-1beta overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPARalpha and hepatic lipase mRNA levels were reduced. PGC-1beta overexpression blunted Wy-mediated changes in expression levels of PPARalpha and downstream genes. Furthermore, PGC-1beta did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1beta and PGC-1alpha overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1beta overexpression decreased hepatic SREBP-1c, yet increased FAS and ACCalpha mRNA and plasma triglyceride levels. CONCLUSIONS: Hepatic PGC-1beta overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1beta overexpression reduced the potentially beneficial effects of PPARalpha activation on gene expression. Thus, inhibition of hepatic PGC-1beta may provide a therapy for treating combined hyperlipidemia.

[8-oxo-7,8-dihydro-2'-deoxyguanosine as a marker of DNA oxidative stress in individuals with combined familiar hyperlipidemia]. / Estudio de los valores de 8-oxo-7,8-dihidro-2'-desoxiguanosina como marcador de estrés oxidativo del ADN en pacientes con hiperlipemia familiar combinada.

BACKGROUND AND OBJECTIVE: To compare 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) value as an indicator of oxidative stress situation between healthy and familial combined hyperlipidemic (FCH) subjects as a mixed dislipidemia with insulin resistance model and early coronary heart disease, and to study its relationship with clinical-biologic parameters of insulin resistance. SUBJECTS AND METHOD: 40 non-related FCH patients (15 women) and 20 normolipidemic and nondiabetic healthy subjects (8 women) were studied. Clinical, anthropometric and biochemical parameters (lipidic profile, glucemia, insulinemia and 8-oxo-dG) were measured in fasting state in all. RESULTS: Both groups had similar age, body mass index blood pressure and waist perimeter values. Insulin and 8-oxo-dG values were significantly higher in FHC subjects. These differences were maintained after correcting by waist perimeter. 8-oxo-dG correlated positively with insulin and trygliceride; and negatively with high density lipoprotein cholesterol in FCH subjects. CONCLUSIONS: Insulin values are independently correlated with oxidative stress degree measured as 8-oxo-dG.

Relationship between familial combined hyperlipidemia and insulin resistance.

BACKGROUND AND AIMS: Familial combined hyperlipidemia is the most frequent hereditary dyslipidemia, usually associated with insulin resistance. Recently, the diagnostic criteria offamilial combined hyperlipidemia were redefined: There should be at least two 1st degree hyperlipidemic relatives with both triglycerides > or = 1.5 mmol x L(-1) and apolipoprotein B > or = 1.20 g L(-1). The aim of this study was to evaluate the relationship between this lipoprotein phenotype and the presence of insulin resistance and to assess the presence of metabolic syndrome. METHODS: Lipid parameters and parameters associated with insulin resistance were determined in 90 subjects of families with familial combined hyperlipidemia and 38 controls. The members of affected families were further divided into the hyperlipidemic and normolipidemic group. RESULTS: The hyperlipidemic group showed only significantly higher fasting proinsulin levels [HL 17,4 +/- 1.5 vs NL 12.8 +/- 1.4 (p = 0.030); and vs CO 11.1 +/- 1.4 (p = 0.003)] in comparison with the normolipidemic and control groups. Differences in fasting insulin [HL 9.40 +/- 0.78 vs NL 7.78 +/- 0.71 (p = NS); and vs CO 7.30 +/- 0.76 (p = NS)], C-peptide [HL 2.56 +/- 0.19 vs NL 2.27 +/- 0.17 (p = NS); and vs CO 2.07 +/- 0.18 (p = NS)], and HOMA [HL 2.16 +/- 0.21 vs NL 1.84 +/- 0.20 (p = NS); and vs CO 1.69 +/- 0.21 (p = NS)] did not reach statistical significance. On the contrary, the members of families with familial combined hyperlipidemia with the presence of metabolic syndrome (NCEP-ATP III) had significantly higher fasting insulin [FCH with MS 12.74 +/- 1.42 vs HL without MS 9.21 +/- 0.92 (p = 0.030); and vs NL without MS 6.75 +/- 0.80 (p = 0.001)], and proinsulin levels [FCH with MS 25.28 vs HL without MS 15.69 +/- 1.75 (p = 0.002); and vs NL without MS 11.20 +/- 1.51 (p = 0.0001)], and HOMA index [FCH with MS 3.03 +/- 0.39 vs HL without MS 2.13 +/- 0.25 (p = 0.042); and vs. NL without MS 1.56 +/- 0.22 (p = 0.003)] in comparison with their relatives without metabolic syndrome and controls. CONCLUSION: The presence of the metabolic syndrome could detect the most insulin resistant subjects in families with familial combined hyperlipidemia who are at increased risk of cardiovascular disease.