This study was undertaken to determine potential tissue sources of plasma cholesteryl ester transfer protein (CETP), and to assess the influence of CETP on lipoprotein concentrations and atherosclerosis. In a group of 28 cynomolgus monkeys fed high fat, high cholesterol diets, plasma CETP concentration was strongly correlated with the abundance of CETP mRNA in liver and in adipose tissue, and with the output of CETP in liver perfusates. Plasma CETP concentration showed a strong inverse correlation with HDL cholesterol concentrations (r = -0.62, P < 0.001) and a positive correlation with LDL cholesterol concentration (r = 0.54, P < 0.005) and molecular weight (r = 0.57, P < 0.001). The extent ofcoronary artery atherosclerosis was positively correlated with LDL cholesterol concentration and molecular weight, and with plasma CETP concentration. Thus, in monkeys fed an atherogenic diet, individual variation in CETP mRNA abundance in liver and adipose tissue probably plays a major role in the determination of plasma CETP levels. In plasma, CETP influences the distribution of cholesteryl esters between LDL and HDL, and CETP concentration appears to be a key determinant of the relative atherogenicity of the plasma lipoproteins. (J. Clin. Invest.

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BackgroundHepatic macrosteatosis (HMS) is prevalent among high BMI patients, but a lack of validation of non-invasive measures of liver fat hampers non-alcoholic liver disease (NAFLD) investigation in general. Recent work suggests BMI adjusted, non-contrasted computed tomography (nc-CT) attenuation data (Hounsfield units) reflects liver fat accumulation in a normal weight population. However, this and other CT-based HMS studies have only approximated macrosteatosis (%) histologically, but have not validated findings with chemical liver triglyceride (TG) concentrations (mg/gram protein). Also, all previous CT based steatosis studies excluded high BMI subjects, whose habitus may affect properties of the scan. We hypothesized that in high BMI patients nc-CT attenuation measurements expressed in Hounsfield units (HU) accurately estimate liver triglyceride concentrations as well as histological macrosteatosis.MethodsWith informed consent, 15 patients underwent nc-CT scan of the abdomen prior to weight loss surgery with intraoperative wedge and core needle liver biopsy. Mean left lobe nc-CT Hounsfield units (CTL), liver TG (mg/g Pr), HMS (%), BMI (kg/m2), liver-spleen index (CTL/S = hepatic HU/splenic HU), and liver–spleen difference (CTL-S = hepatic HU − splenic HU) were a priori outcomes.ResultsIn 15 patients (11 female) with a BMI of 44.4 ± 1.1 (mean ± SEM), CTL/S, CTL-S, and CTL measures were significantly associated with liver TG concentrations (r = −0.80, P < 0.001; r = −0.80, P < 0.001; and r = −0.71, P < 0.01, respectively; Table 1). Macrosteatosis (%) and liver triglyceride concentration were positively associated (r = 0.83; P < 0.0001). BMI did not correlate strongly to liver triglyceride (r = 0.44, P = NS).ConclusionEstimates of liver fat obtained by nc- CT scans (esp. CTL/S, CTL-S) correlate to chemical measurement of liver triglyceride concentrations, suggesting non-contrasted CT may be a suitable non-invasive “gold standard” for hepatic steatosis quantification in these patients.

Male Macaca nemestrina were studied In an experiment with a 2 X 2 factorial design. Diets contained low vs high cholesterol levels (0.3 vs 1.0 mg/Kcal) and no ethanol or ethanol, as 36% of the calories substituted isocalorically for carbohydrate. After receiving their diets for 18 months, the monkeys had blood samples drawn for lipoproteln analyses, and then were killed for evaluation of the extent of atherosclerosis. Ethanolfed groups had significantly Increased concentrations of serum cholesterol, triglycerides, low density lipoproteln, and high density lipoprotein. The molecular weight of the low density lipoprotein particles was lower In ethanol-fed animals and the cholesterol esters of low density lipoproteln and high density lipoprotein contained relatively more cholesteryl linoleate and less cholesteryl oleate. Dietary cholesterol had the effect of increasing the concentration of low density lipoprotein (primarily via increasing the low density lipoprotein molecular weight) and decreasing the concentration of high density lipoproteln. Significant Interactions were found between the effects of ethanol and cholesterol on high density lipoprotein and low density lipoprotein. Ethanol significantly decreased the cholesterol-Induced atherosclerosis found in the aorta and coronary arteries. Highly significant correlations between coronary artery atherosclerosis and low density lipoproteln molecular weight, Inverse high density lipoproteln concentration, and low density lipoprotein cholesterol ester pattern were found. In contrast, low density lipoproteln molar concentration (number of low density lipoproteln particles per liter of plasma) was not significantly correlated with coronary artery atherosclerosis. Different relationships with aortic atherosclerosis were found; low density lipoproteln molecular weight and cholesterol ester pattern were highly correlated, while high density lipoproteln concentration was not. The high correlations found between lipoproteln characteristics and atherosclerosis severity suggest that the effect of ethanol in reducing the development of atherosclerosis may have been mediated through Its effects on the plasma llpoprotelns. (Arteriosclerosis 1981; 1:144-155)