Plasma ALT can explain 14·2% of the strong association between insulin resistance and circulating concentrations of complement C3, independent of central obesity and general inflammation.

Objective-The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses. Methods and Results-Hyperlipidemic FCHL relatives (nϭ72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size Ͻ258 Å) and pattern A LDL (buoyant LDL, particle size Ն258 Å) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, nϭ7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A. Key Words: sd LDL Ⅲ apolipoprotein B Ⅲ triglycerides Ⅲ insulin resistance Ⅲ VLDL F amilial combined hyperlipidemia (FCHL) is a metabolic disease, delineated as a genetic disorder of lipid metabolism almost 3 decades ago. 1 It is associated with a 2-to 5-fold increased risk of premature coronary artery disease. 1,2 Despite recent progress, the genetic and metabolic backgrounds of FCHL have not been elucidated in detail. Subjects with FCHL present with a complex phenotype whose expression is influenced by genetic, metabolic, and environmental factors. [3][4][5][6] Affected FCHL relatives are viscerally obese, 2,4,7 hyperinsulinemic, 3 insulin-resistant, 5,7 and can show a number of abnormalities in lipid metabolism: hypercholesterolemia and/or hypertriglyceridemia, elevated apolipoprotein B (apoB) levels, small dense low-density lipoprotein (sd LDL), and decreased plasma high-density lipoprotein (HDL) cholesterol concentrations. Conclusions-TheVery low-density lipoprotein (VLDL) and LDL consist of distinct, physicochemically heterogenic subclasses. 8 A practical characterization of the LDL profile divides it into two major phenotypes: pattern A, characterized by a preponderance of large, buoyant particles, with peak particle diameter Ն258 Å, and pattern B, characterized by predominance of sd LDL particles, with peak particle diameter Ͻ258 Å. In the population, sd LDL phenotype and the concurrent metabolic abnormalities (relative hypertriglyceridemia and low HDL cholesterol) have been designated the atherogenic lipoprotein phenotype, 9 consistent with its association with an increased risk of coronary artery disease. 9,10 Furthermore, pattern B LDL has been recognized as a feature of the metabolic syndrome 11 and is characteristic for i...

Our results strengthen the evidence that one or more variants in ATF6 are associated with disturbed glucose homeostasis and DM2.

This is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia.

The inbred HcB19 mouse strain expresses a truncated form of thioredoxin interacting protein and is phenotypically characterized by fatty liver and elevated plasma triglycerides and VLDL. Recently, these mice have been proposed as an animal model for familial combined hyperlipidemia. The aim of the present study was identification of hepatic proteins specifically associated with the presence of fatty liver. Eighteen differential proteins were detected in whole-liver homogenate from HcB19, or the parental strain C3H, using 2D electrophoresis, and 11 of those were successfully identified by mass spectrometry. Five of the identified differential proteins were mitochondrial, two peroxisomal, two cytosolic, and two secretory.

The present study shows that the longitudinal relation abdominal obesity-ALT is more specific for all FCHL family members, i.e. patients and their normolipidemic relatives, than the relation abdominal obesity-triglycerides. Additionally,the association of ALT with the switch in triglyceride phenotype suggests a central role of the liver in the pathogenesis of FCHL.

No abstract

The aim of this study was to evaluate whether soluble factors in plasma of familial combined hyperlipidemia (FCHL) patients affect hepatic protein secretion. Cultured human hepatocytes, i.e., HepG2 cells, were incubated with fasting plasma (20%, v/v, in DMEM) from untreated FCHL patients or normolipidemic controls. Overall protein secretion was 10-15% higher after incubation with FCHL plasma. This was specifically caused by an increase in four secreted proteins, with estimated sizes of 240, 180, 120, and Ͻ 40 kD ( P Ͻ 0.001, P Ͻ 0.006, P Ͻ 0.002, P Ͻ 0.02, respectively). The 240 kD protein in the secretion proteome was identified as fibronectin by mass spectrometry. Plasma fibronectin concentrations were elevated in FCHL patients, confirming biological relevance of these data. Overall protein secretion by HepG2 cells correlated with concentrations of triglycerides ( r ‫؍‬ 0.61, P Ͻ 0.001) in the applied plasma samples. VLDL ؉ IDL isolated from FCHL patients, induced a higher protein secretion than lipoproteins isolated from controls ( P Ͻ 0.001). Remarkably, secretion of apoB, the structural protein of VLDL, was stimulated to a similar extent by FCHL and control plasma. Familial combined hyperlipidemia (FCHL) is a common dyslipidemia with a strong genetic component. The prevalence of FCHL in the population is 1-2% and FCHL is estimated to cause 10-20% of premature coronary heart disease (CHD) (1). Metabolic disturbances in FCHL include overproduction of atherogenic apolipoprotein B (apoB)-containing lipoproteins (i.e., VLDL), delayed clearance of lipoproteins, increased plasma apoB concentrations, increased free fatty acid (FFA) fluxes, and insulin resistance. The molecular mechanism(s) that underlie these metabolic abnormalities are not yet known. It has been suggested that increased plasma FFA fluxes, potentially induced by insulin resistance, may increase hepatic secretion of apoB containing lipoproteins. However, available data on the direct effects of increased FFA fluxes on hepatic apoB production in normal human subjects are limited and apparently conflicting (2, 3). These data do not yet allow defenitive conclusions on the hepatic abnormality in FCHL.The liver plays a central role in the development of atherosclerosis (4). It is an important source of vaso-active compounds as well as atherogenic, apoB containing lipoproteins. Current knowledge on intrahepatic assembly of apoB containing lipoproteins mainly derives from studies in laboratory animals and cells in culture (5). Following intracellular association of lipid with apoB, the precursor lipoproteins fuse with lumenal triglyceride droplets to form mature VLDL that is secreted from the cells (6). The scarce availability of hepatocytes from human FCHL patients renders it not feasible to directly study the role of the liver-specific pathways in FCHL in vitro. It is presently unresolved whether the hepatic hypersecretion of lipoproteins that is observed in FCHL is a process inherent to metabolic abnormalities in the liver, or may be driven by s...