VLDL-TG Production Rate Research Articles

Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E- deficient mouse hepatocytes.

To explore mechanisms underlying triglyceride (TG) accumulation in livers of chow-fed apo E-deficient mice (Kuipers, F., J.M. van Ree, M.H. Hofker, H. Wolters, G. In't Veld, R.J. Vonk, H.M.G. Princen, and L.M. Havekes. 1996. Hepatology. 24:241-247), we investigated the effects of apo E deficiency on secretion of VLDL-associated TG (a) in vivo in mice, (b) in isolated perfused mouse livers, and (c) in cultured mouse hepatocytes. (a) Hepatic VLDL-TG production rate in vivo, determined after Triton WR1339 injection, was reduced by 46% in apo E-deficient mice compared with controls. To eliminate the possibility that impaired VLDL secretion is caused by aspecific changes in hepatic function due to hypercholesterolemia, VLDL-TG production rates were also measured in apo E-deficient mice after transplantation of wild-type mouse bone marrow. Bone marrow- transplanted apo E-deficient mice, which do not express apo E in hepatocytes, showed normalized plasma cholesterol levels, but VLDL-TG production was reduced by 59%. (b) VLDL-TG production by isolated perfused livers from apo E-deficient mice was 50% lower than production by livers from control mice. Lipid composition of nascent VLDL particles isolated from the perfusate was similar for both groups. (c) Mass VLDL-TG secretion by cultured apo E-deficient hepatocytes was reduced by 23% compared with control values in serum-free medium, and by 61% in the presence of oleate in medium (0. 75 mM) to stimulate lipogenesis. Electron microscopic evaluation revealed a smaller average size for VLDL particles produced by apo E-deficient cells compared with control cells in the presence of oleate (38 and 49 nm, respectively). In short-term labeling studies, apo E-deficient and control cells showed a similar time-dependent accumulation of [3H]TG formed from [3H]glycerol, yet secretion of newly synthesized VLDL-associated [3H]TG by apo E-deficient cells was reduced by 60 and 73% in the absence and presence of oleate, respectively. We conclude that apo E, in addition to its role in lipoprotein clearance, has a physiological function in the VLDL assembly-secretion cascade.

Why Do Low-Fat High-Carbohydrate Diets Accentuate Postprandial Lipemia in Patients With NIDDM?

To understand why low-fat high-carbohydrate (CHO) diets lead to higher fasting and postprandial concentrations of triglyceride (TG)-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients with NIDDM were placed randomly on diets containing either 55% CHO, 30% fat, and 15% protein or 40% CHO, 45% fat, and 15% protein for 6 weeks, followed by crossover to the other diet. Test meals at the end of each diet period were consumed at 8:00 A.M. and 12:00 P.M. (noon) and contained 20 and 40% of daily calories, respectively. Vitamin A was also given at noon, and TG-rich lipoproteins of intestinal origin were identified by the presence of vitamin A esters. Frequent measurements were made throughout the 24-h study period of plasma glucose, insulin, and TG concentrations. Plasma samples obtained from 12:00 P.M. (noon) until 12 A.M. (midnight) were subjected to ultracentrifugation, and measurements were made of TG and vitamin A ester concentrations in plasma and in both the Svedberg flotation constant (Sf) > 400 (chylomicron) and Sf 20-400 (chylomicron remnant) lipoprotein fractions. In addition, very-low-density lipoprotein (VLDL)-TG turnover rate was estimated by following the decay of [3H]VLDL-TG. Finally, postheparin lipoprotein lipase and hepatic lipase activities were measured at the end of each dietary period. Mean +/- SE hourly concentrations of glucose (8.0 +/- 0.8 vs. 7.5 +/- 0.7 mmol/l), insulin (184 +/- 26 vs. 158 +/- 19 pmol/l), and TG (2.8 +/- 0.2 vs. 2.1 +/- 0.2 mmol/l) were higher (P < 0.05-0.001) after the 55% CHO diet. The 55% CHO diet also led to an increase (P < 0.05-0.01) in the mean +/- SE hourly concentrations of vitamin A esters in plasma (2.3 +/- 0.3 vs. 1.6 +/- 0.1 mumol/l) and in both the chylomicron (2.0 +/- 0.3 vs. 1.4 +/- 0.1 mumol/l) and chylomicron remnant fractions (0.36 +/- 0.04 vs. 0.14 +/- 0.03 mumol/l). In addition, the VLDL-TG production rate was higher (17.2 +/- 1.4 vs. 12.8 +/- 1.0 mg.kg-1.h-1, P < 0.003) and the VLDL-TG fractional catabolic rate lower (0.22 +/- 0.02 to 0.28 +/- 0.02 l/h, P < 0.005) after the 55% CHO diet. Finally, there was an increase in lipoprotein lipase activity (7.0 +/- 0.8 to 8.1 +/- 0.7 mumol free fatty acids released .ml-1.h-1, P < 0.02) in response to the CHO-enriched diet. A low-fat high-CHO diet in patients with NIDDM led to 1) higher day-long plasma glucose, insulin, and TG concentrations; 2) postprandial accumulation of TG-rich lipoproteins of intestinal origin; 3) increased production of VLDL-TG; and 4) increased postheparin lipoprotein lipase activity. These data provide a mechanism for the hypertriglyceridemic effect of CHO-enriched diets in patients with NIDDM and demonstrate that multiple risk factors for coronary heart disease are accentuated when these individuals consume diets recommended to reduce this risk.

Lipid metabolism in non-insulin-dependent diabetes: effects of long-term treatment with fructose-supplemented mixed meals

Using fructose in the diabetic diet remains controversial primarily because of the potential for adverse effects on serum lipids. Therefore, lipid metabolism was evaluated in five NIDDM subjects (as inpatients) for 3 mo before and after ingestion of mixed meals containing 13% of calories as fructose. Triglyceride (TG) transport in very-low-density lipoproteins (VLDL) was assessed by multicompartmental analysis of VLDL-TG specific activity after injection of 3H-2-glycerol. There were no deleterious changes in lipid metabolism after fructose supplementation. The fructose diet produced no changes in serial free fatty acids (from 0.39 +/- 0.04 to 0.51 to 0.12 mmol/L), total cholesterol (from 5.43 +/- 0.52 to 5.53 +/- 0.57 mmol/L), high-density lipoproteins (from 0.91 +/- 0.08 to 0.93 +/- 0.08 mmol/L), low-density lipoproteins (from 3.10 +/- 0.52 to 2.92 +/- 0.47 mmol/L), VLDL-TG production (from 2.11 +/- 0.36 to 2.07 +/- 0.30 mmol/h), and fractional catabolic rate (from 0.186 +/- 0.014 to 0.196 +/- 0.03/h). Physiologic amounts of fructose are unlikely to have adverse effects on lipid metabolism when consumed by these diabetic subjects in place of sucrose in mixed meals for a prolonged period.

Very low-density lipoprotein metabolism in an unusual case of lipoatrophic diabetes

Complete acquired lipoatrophic diabetes (LD) is characterized by nonketotic insulin-resistant diabetes, elevated very low-density lipoprotein (VLDL) triglyceride (TG) levels, and absent subcutaneous fat. We studied a young child in whom LD atypically developed after the onset of type 1 diabetes mellitus. On uncontrolled home diet the patient had triglyceride levels over 1,000 mg/dL on multiple occasions. In order to demonstrate the effects of caloric and dietary-fat restriction on VLDL metabolism, 3H-glycerol and autologous 125I-VLDL were used to quantitate the turnover of VLDL-TG and VLDL-apolipoprotein B (apo B) during two periods of caloric restriction. Consumption of a 900-kcal 40-g fat diet resulted in a plasma triglyceride level of 1383 mg/dL (ten-fold elevation). This hypertriglyceridemia was associated with markedly increased production rates of both VLDL-TG (73.7 mg/kg/h) and VLDL-apo B (126.9 mg/kg/d). Consumption of a 900-kcal 25-g fat diet resulted in a plasma TG level of 663 mg/dL. This reduction in plasma TG was associated with a 40% decrease in VLDL-TG production rate (PR) (45.1 mg/kg/h). There was no change in the production rate (PR) of VLDL-apo B. The hypertriglyceridemia in this patient was due to marked over production of VLDL. Furthermore, the studies demonstrate: (1) the independent benefits of caloric and dietary-fat restriction in the treatment of LD, and (2) that fat restriction lowered plasma triglyceride by its effect on the VLDL-TG production rate.

Effect of obesity on the relationship between very low density lipoprotein production rate and plasma triglyceride concentration in normal and hypertriglyceridemic subjects

The effect of obesity on the relationship between very low density lipoprotein (VLDL)-triglyceride (TG) production rate and concentration was studied in 80 subjects whose TG concentrations ranged from 41–1315 mg 100 ml and whose relative weight varied from 0.74–1.46. There was a positive correlation between VLDL-TG production rate and plasma TG concentration in all 80 patients ( r = 0.78), which was highly statistically significant ( p < 0.001). Both male and female subjects were subdivided into quartiles on the basis of relative weight; the relationship between VLDL-TG production rate and plasma TG concentration was found to be comparable in all subgroups. These observations suggest that moderate degrees of obesity do not affect VLDL-TG kinetics in patients whose plasma TG levels vary over an extremely wide range.

Reappraisal of the role of insulin in hypertriglyceridemia

We have previously proposed a sequential hypothesis to help explain the genesis of endogenous hypertriglyceridemia in man. This scheme states that insulin resistance → hyperinsulinemia → increased very low density lipoprotein (VLDL)-triglyceride (TG) production rate → increased plasma TG levels. In this study we have measured each of these metabolic variables in 34 nonobese subjects all consuming the same isocaloric diet. We have found highly significant positive correlations between insulin resistance and insulin response (r = 0.74, p < 0.0001), between insulin response and VLDL-TG production rate (r = 0.72, p < 0.0001), and between VLDL-TG production rate and plasma TG level (r = 0.88, p < 0.0001). Furthermore, these relationships were found to be independent of any possible effect of obesity. Thus, highly positive correlations were found for each step of the scheme, and we believe the over-all hypothesis is greatly strengthened. Additionally, the cross correlation between plasma TG levels and insulin response was also highly significant (r = 0.73, p < 0.0001). On the other hand, glucose response did not correlate with any measure of TG metabolism. On the basis of these results we conclude that insulin plays an important role in the genesis of endogenous hypertriglyceridemia through its influence on VLDL-TG production.

Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects.

Considerable controversy exists over the purported role of obesity in causing hyperglycemia, hyperlipemia, hyperinsulinemia, and insulin resistance; and the potential beneficial effects of weight reduction remain incompletely defined. Hypertriglyceridemia is one of the metabolic abnormalities proposed to accompany obesity, and in order to help explain the mechanisms leading to this abnormality we have proposed the following sequential hypothesis: insulin resistance --> hyperinsulinemia --> accelerated hepatic triglyceride(TG) production --> elevated plasma TG concentrations. To test this hypothesis and to gain insight into both the possible role of obesity in causing the above metabolic abnormalities and the potential benefit of weight reduction we studied the effects of weight loss on various aspects of carbohydrate and lipid metabolism in a group of 36 normal and hyperlipoproteinemic subjects. Only weak to absent correlations (r = 0.03 - 0.46) were noted between obesity and the metabolic variables measured. This points out that in our study group obesity cannot be the sole, or even the major, cause of these abnormalities in the first place. Further, we have observed marked decreases after weight reduction in fasting plasma TG (mean value: pre-weight reduction, 319 mg/100 ml; post-weight reduction, 180 mg/100 ml) and cholesterol (mean values: pre-weight reduction, 282 mg/100 ml; post-weight reduction, 223 mg/100 ml) levels, with a direct relationship between the magnitude of the fall in plasma lipid values and the height of the initial plasma TG level. We have also noted significant decreases after weight reduction in the insulin and glucose responses during the oral glucose tolerance test (37% decrease and 12% decrease, respectively). Insulin and glucose responses to liquid food before and after weight reduction were also measured and the overall post-weight reduction decrease in insulin response was 48% while the glucose response was relatively unchanged. In a subgroup of patients we studied both the degree of cellular insulin resistance and the rate of hepatic very low density (VLDL) TG production before and after weight reduction. These subjects demonstrated significant decreases after weight reduction in both degree of insulin resistance (33% decrease) and VLDL-TG production rates (40% decrease). Thus, weight reduction has lowered each of the antecedent variables (insulin resistance, hyperinsulinemia, and VLDL-TG production) that according to the above hypothesis lead to hypertriglyceridemia, and we believe the overall scheme is greatly strengthened. Furthermore, the consistent decreases in plasma TG and cholesterol levels seen in all subjects lead us to conclude that weight reduction is an important therapeutic modality for patients with endogenous hypertriglyceridemia.