Josef R. Patsch

Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state.

The status of fasting triglycerides as a risk factor for coronary artery disease (CAD) has been considered weak because in multivariate analyses, triglycerides tend to be eliminated by high density lipoprotein (HDL) cholesterol. To further evaluate the role of triglycerides in CAD, we employed postprandial lipemia as a more informative means of characterizing triglyceride metabolism. In 61 male subjects with severe CAD and 40 control subjects without CAD as verified by angiography, we measured cholesterol; triglycerides; HDL cholesterol; HDL2 cholesterol; and apolipoproteins A-I, A-II, and B in fasting plasma and triglycerides before and 2, 4, 6, and 8 hours after a standardized test meal. Both the maximal triglyceride increase and the magnitude of postprandial lipemia (area under the triglyceride curve over 8 hours after the meal) were higher in cases than in control subjects. Single postprandial triglyceride levels 6 and 8 hours after the meal were highly discriminatory (p < 0.001), and by logistic-regression analysis displayed an accuracy of 68% in predicting the presence or absence of CAD. In this respect, accuracy was higher than that of HDL2 cholesterol (64%) and equal to that of apolipoprotein B (68%), the most discriminatory fasting parameter. Multivariate logistic-regression analysis was performed to reduce the number of risk factors to those that were statistically independent. This statistical procedure selected postprandial but not fasting triglycerides into the most accurate multivariate model, which also contained the accepted risk factors HDL2 cholesterol, apolipoprotein B, and age. This model classified 82% of subjects correctly. We conclude that triglycerides are independent predictors of CAD in multivariate analyses including HDL cholesterol, provided that a challenge test of triglyceride metabolism such as postprandial lipemia is used. The study suggests that the metabolism of triglycerides is a critical determinant of cholesterol metabolic routing. The findings support the concept that the negative association between HDL cholesterol levels and CAD actually originates in part from a positive relation between CAD and plasma triglycerides, as ascertained in the postprandial state.

Effects of Dietary Polyunsaturated and Saturated Fat on the Properties of High Density Lipoproteins and the Metabolism of Apolipoprotein A-I

In this study we have investigated, in four normal males the effects of dietary saturated and polyunsaturated fat on the chemical composition and thermotropic properties of human high density lipoproteins (HDL) and have measured the influence of the diets on the metabolism of that fraction of HDL apolipoprotein A-I (apoA-I) that undergoes exchange in vitro and accounts for approximately two-thirds of the lipoproteins apoA-I complement. When compared with the saturated fat diet, the polyunsaturated diet reduced plasma cholesterol (24%, P < 0.01) by affecting the cholesterol content in the very low density lipoprotein ( downward arrow25%, P < 0.02), low density lipoprotein ( downward arrow20%, P < 0.01), and high density lipoprotein fractions ( downward arrow33%, P < 0.01). Plasma triglyceride was also lowered (by 13%, P < 0.01). Furthermore, polyunsaturated fat ingestion caused a significant fall in the palmitate and stearate content of HDL triglyceride (41 and 37%, respectively), cholesteryl esters (29 and 35%), and phospholipids (17 and 9%) with a concomitant increase in the linoleate content of these moieties (157, 28, and 29%, respectively). The polyunsaturated diet also produced reciprocal changes in the percentage protein ( downward arrow9%, P < 0.02) and phospholipid ( downward arrow11.5%, P < 0.01) in HDl. These compositional changes were associated with an increase in the microscopic fluidity of the polyunsaturated HDL, although both diets had little effect on the fluidity parameters of HDL at body temperature. Rate zonal ultracentrifugation indicated that the HDL(2)/HDL(3) ratio fell by 28% (P < 0.05) on the polyunsaturated fat diet. In addition to the above, this diet reduced plasma apoA-I by 21% (P < 0.01). No change was seen in the fractional catabolic rate or the distribution of the apoprotein between intravascular and extravascular compartments on the two diets. However, when compared with the saturated diet, the synthetic rate of apoA-I was reduced by 26% during polyunsaturated fat feeding. The results show that polyunsaturated fat alters the chemical composition, thermotropic properties, and subfraction distribution of HDL without changing the fractional rate of catabolism of their major protein, apoA-I.These findings deserve careful consideration in determining the applicability and efficacy of polyunsaturated fat diet therapy in the prevention of atherosclerosis in man.

Adiponectin and its receptors in non-alcoholic steatohepatitis

Background: Adiponectin, an adipocyte derived polypeptide, has been shown to alleviate steatosis and inflammation in mice with non-alcoholic fatty liver disease. Aim: In the present study, we wished to define liver expression of adiponectin and its receptors in morbidly obese patients undergoing bariatric surgery. Patients with non-alcoholic steatohepatitis (NASH) or simple steatosis were investigated to test whether dysregulation of this system might be involved in these disorders. Patients and methods: Liver mRNA expression of adiponectin and its recently cloned receptors RI and RII (adipoRI and adipoRII) were analysed by fluorescence based real time polymerase chain reaction in 13 patients with NASH and nine with simple steatosis. Adiponectin and adipoRII protein expression were assessed by immunohistochemistry in a subgroup of patients. Results: Adiponectin and adipoRII mRNA expression were significantly reduced in liver biopsies of patients with NASH compared with simple steatosis while no difference was found in adipoRI mRNA expression. In NASH, adipoRII mRNA expression was negatively correlated with serum aspartate aminotransferase levels, serum alanine aminotransferase levels, and grade of fibrosis. Liver adiponectin protein expression was mainly found in endothelial cells of portal vessels and liver sinusoids whereas adipoRII expression was seen in hepatocytes only. Adiponectin and adipoRII staining were lower in biopsies of subjects with NASH compared with simple steatosis. Conclusion: Reduced hepatic expression of adiponectin and adipoRII might be of pathophysiological relevance in non-alcoholic fatty liver diseases.

High density lipoprotein2. Relationship of the plasma levels of this lipoprotein species to its composition, to the magnitude of postprandial lipemia, and to the activities of lipoprotein lipase and hepatic lipase.

Lipoprotein lipase (LPL) activity in postheparin plasma of 38 normolipidemic volunteers was related to the magnitude of postprandial lipemia after a fat meal, to triglyceride content of high density lipoprotein2 (HDL2), to hepatic lipase (HL) activity, and to HDL2 levels. LPL activity correlated indirectly with lipemia, triglyceride content of HDL2, HL activity, and levels of HDL2 but not of HDL3. HL activity correlated directly with lipemia and indirectly with HDL2 levels. Triglyceride content of HDL2 correlated directly with lipemia and indirectly with HDL2 levels. In HDL2, abundance of apolipoprotein (apo) A-II and the apoA-I/apoA-II ratio varied widely. The latter correlated positively with LPL activity and HDL2 levels, and, inversely, with HL activity, lipemia, and triglyceride content of HDL2. The study suggests that HDL-cholesterol is not an independent parameter of lipid transport, but is strongly affected by triglyceride metabolism through lipolytic enzymes, as exemplified by postprandial lipemia that affect both composition and plasma levels of HDL2.

A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (∼63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

Postprandial lipemia. A key for the conversion of high density lipoprotein2 into high density lipoprotein3 by hepatic lipase.

In this study, we have investigated the effects of alimentary lipemia in 15 normotriglyceridemic individuals on high density lipoproteins2 (HDL2) with respect to structure, composition, and substrate efficacy for hepatic lipase in vitro. In the study subjects, HDL2 levels ranged widely from 4.7 to 151.7 mg/dl plasma. HDL2 were isolated in the postabsorptive (pa) state and in the postprandial (pp) state, i.e., 7 h after ingestion of a standard fatty meal. In going from the pa state to the pp state, HDL2 exhibited higher flotation rates and lower densities due to a decreased proportion of protein (38.7----36.2%) and a higher abundance in phospholipid (32.5----34.9%). There was a variable increase in triglyceride at the expense of cholesteryl esters; this increase was correlated positively with the magnitude of pp lipemia (r = 0.69, P less than 0.01) and inversely with HDL2 levels (r = -0.72, P less than 0.01). Hdl2 fractions were incubated with human hepatic lipase in vitro. Product lipoproteins formed from lipolysis of pa-HDL2 and triglyceride-poorer pp-HDL2 were reduced in phospholipid content (by 25 and 50%, respectively) but remained in the size and density range of native HDL2. By contrast, a major fraction of triglyceride-richer pp-HDL2 was converted to particles with density, size, and apoprotein composition of native HDL3. Changes consistent with these findings in vitro were observed in vivo also, where 15 h postprandially, individuals with high-level lipemia showed a decrease in HDL2 and rise in HDL3, while those with lower-level lipemia did not. This study indicates that the magnitude of postprandial lipemia determines the proportion of triglyceride in pp-HDL2, which in turn determines whether or not HDL2 are converted to HDL3 by hepatic lipase action.

Metabolic side effects of antipsychotic medication.

The use of second‐generation antipsychotics (SGAs) is associated with metabolic side effects including weight gain, diabetes mellitus and an atherogenic lipid profile. These adverse effects are not only the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus leading to increased morbidity and mortality but may also impair the patients adherence to treatment.

Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention

Background: Human adipose tissue expresses and releases proinflammatory cytokines and these measures of chronic inflammation have recently been associated with obesity.Hypothesis: To test whether the proinflammatory state is reversible in subjects undergoing weight loss by surgical measures.Subjects and Methods: Twenty morbidly obese women participated in this prospective study. Subjects were examined for fat mass, high-sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) before and 1 y after Swedish adjustable gastric banding.Results: Anthropometric measures displayed a significant reduction of the body mass index (BMI) from 41.6±5.4 to 30.8±6.1 kg/m2 and the fat mass from 53.9±10.3 to 29.8±12.1 kg (mean±s.d.). Hs-CRP levels decreased significantly from 1.33±1.21 mg/dl in pre-gastric banding subjects to 0.40±0.61 mg/dl in post-gastric banding subjects, respectively. IL-6 and TNF-α levels did not differ significantly between pre- and post-gastric banding subjects.Conclusions: We speculate that in these patients the marked reduction in C-reactive protein might be beneficial in reducing their cardiovascular risk and is not solely mediated by IL-6 and TNF-α.

Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis

OBJECTIVES We studied associations between iron status and early functional and structural vascular abnormalities in patients with hereditary hemochromatosis (HH). BACKGROUND Iron may be involved in atherogenesis, and patients bearing a genetic mutation associated with HH are possibly at risk of developing coronary heart disease. METHODS We studied the vascular properties of 41 HH patients who had homozygosity for the C282Y mutation, along with 51 age-matched control subjects, by determination of endothelium-dependent dilation (EDD) of the brachial artery and intima-media thickness (IMT) of the carotid artery. RESULTS Male HH patients who were not receiving phlebotomy therapy showed a reduced EDD and increased IMT compared with controls and HH patients receiving therapy. In female HH patients, irrespective of treatment status, vascular parameters were not different from those of controls, and none of these patients had severe iron overload. In HH patients, increased iron load was significantly associated with reduced EDD and increased IMT. Moreover, we found a positive correlation between body iron stores and indicators of oxidative stress. When previously untreated male HH patients were re-investigated after intensive phlebotomy therapy, a significant improvement in EDD was observed (2.6 +/- 1.3% before vs. 5.5 +/- 2.1% after treatment, p = 0.0015). CONCLUSIONS Impaired endothelial function and increased IMT are associated with iron overload, with subsequent induction of oxidative stress, and are not linked to a genetic disability in HH patients. Consequent iron-depletion therapy normalizes endothelial function and may thus reduce the increased risk of cardiovascular events. Female patients may be at a reduced risk, presumably due to continuous iron loss by menstruation.

Postprandial state and atherosclerosis

Accumulating evidence suggests that triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis. This epidemiological evidence first emerged as a result of studying postprandial lipaemia that characterized the metabolic capacity of triglycerides in the postabsorptive state, that is, under challenge. Studies of postprandial lipaemia were helpful to explain several effects of triglyceride-rich lipoproteins on cholesteryl-ester-rich lipoproteins. From these studies it became apparent that peculiarities of cholesteryl-ester-rich lipoproteins, such as small LDL and small HDL, which have been associated with risk for atherosclerosis, were caused by impaired triglyceride metabolism.