Reduction In Plasma Triglyceride Concentrations Research Articles

Unanticipated Enhancement of Intestinal TG Output by Apoc3 ASO Inhibition.

The objective of this study was to investigate whether apoC3 (apolipoprotein C3) inhibition with an antisense oligonucleotide (ASO) modulates intestinal triglyceride secretion. Sprague-Dawley rats were treated with subcutaneous injections of apoC3 ASO 25 mg/kg twice weekly or inactive ASO for 4 weeks before the assessment of lymph flow, triglyceride and apoB48 appearance in the lymph. Rats were surgically implanted with catheters in the mesenteric lymph duct and duodenum. Following an overnight fast, an intraduodenal lipid bolus (1.5-mL intralipid) was administered. Lymph fluid was collected for the following 4 hours to compare effects on lymph flow, lymph triglyceride and apoB48 concentration, and secretion. To assess suppression of apoC3 expression and protein abundance by apoC3 ASO compared with inactive ASO (placebo), intestinal and hepatic tissues were collected from a subset of animals before (fasting) and after an enteral lipid bolus (post-lipid). ApoC3 ASO significantly reduced apoC3 mRNA expression in the liver compared with inactive ASO (fasting: 42%, P=0.0048; post-lipid: 66%, P<0.001) and in the duodenum (fasting: 29%, P=0.0424; post-lipid: 53%, P=0.0120). As expected, plasma triglyceride also decreased significantly (fasting: 74%, P<0.001; post-lipid: 33%, P=0.0276). Lymph flow and cumulative lymph volume remained unchanged following apoC3 ASO therapy; however, lymph triglyceride, but not apoB48 output, increased by 38% (ANOVA, P<0.001). Last, no changes were observed in stool triglyceride, intestinal fat (quantified via oil red O staining), and expression of mRNAs involved in triglyceride synthesis, lipid droplet formation, and chylomicron transport and secretion. Despite the marked reduction in plasma triglyceride concentration that occurs with apoC3 ASO inhibition, intestinal triglyceride output surprisingly increased rather than decreased. These data demonstrate that the reduction of intestinal triglyceride output does not contribute to the potent plasma triglyceride-lowering observed with this novel therapy for hypertriglyceridemia. Further studies are required to explore the mechanism of this intestinal effect.

Thioesterase superfamily member 2 (Them2) Regulates Fatty Acid Partitioning Between Oxidative and Secretory Pathways in the Liver

Them2 (synonym: Acyl‐CoA thioesterase 13) is a mitochondria‐associated long‐chain acyl‐CoA thioesterase that is abundant in the liver and oxidative tissues. Evidence from whole‐body knockout mice suggests that Them2 prevents diet‐induced hepatosteatosis and improves hepatic glucose homeostasis. In cultured hepatocytes, Them2 promotes fatty acid oxidation and decreases lipogenesis. However, because it also suppresses thermogenesis in brown adipose tissue by limiting fatty acid oxidation, the true contribution to fatty acid metabolism of Them2 in the liver remains unclear. In order to evaluate the role of Them2 in liver to fatty acid metabolism, we created Them2 liver‐specific knockout (L‐Them2−/−) mice, which were fed chow or high fat diet for 12 weeks. L‐Them2−/− mice exhibited similar weight gain, body mass composition and glucose homeostasis in comparison to control animals. Whereas the rates of fatty acid uptake, de novo fatty acid synthesis, and hepatic concentrations of free fatty acids were unchanged, hepatic fatty acid oxidation was increased by 30% in chow‐fed L‐Them2−/− mice. In the absence of changes in steady concentrations of hepatic triglyceride and glycerolipid synthetic rates, a reduction in plasma triglyceride concentrations was observed upon hepatic Them2 ablation (38 and 43% decrease in chow and high fat fed, respectively). This was associated with a reduction in plasma VLDL‐triglyceride concentrations (29 and 9% in chow and high fat fed mice, respectively). Chow fed L‐Them2−/− mice also exhibited a 26% reduction in plasma apoB100 concentrations and a marked (70%) reduction in hepatic VLDL‐triglyceride secretion rates. Taken together, these data suggest that hepatic Them2 functions to direct fatty acids towards triglyceride incorporation into VLDL particles for secretion and away from mitochondrial β‐oxidation, thereby sustaining the export of lipids from the liver to the plasma and peripheral tissues. We speculate that Them2 in the liver plays a key role in determining the metabolic fates of fatty acids in response to nutritional status and metabolic demands.Support or Funding InformationThis work was supported by NIH R37 DK048873 and R01 DK056626 to D.E.C. M.A.‐B. was the recipient of a NASH Fatty Liver Disease Postdoctoral Research Fellowship Award from the American Liver Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Treating fatty liver and insulin resistance

Treating fatty liver and insulin resistance

Treatment of Hypertriglyceridemia in Patients Receiving Parenteral Nutrition

This study aims to evaluate whether withdrawal of a soy oil-based lipid emulsion from the parenteral nutrition (PN) regimen in humans is associated with improved triglyceride and liver enzyme concentrations. In this retrospective study, patients with hypertriglyceridemia (>4.50 mmol/L) while receiving PN were retrieved from a prospective complication registration database. Patients received Intralipid 20% as part of an all-in-one system containing all necessary macro- and micronutrients, electrolytes, trace elements, and vitamins. Forty patients with hypertriglyceridemia were included. Lipid emulsions were withdrawn from the all-in-one mixture for a median of 5 (range, 1-23) days, after which triglyceride concentrations decreased significantly (mean difference -2.5 ± 0.30 mmol/L, P < .001). Aspartate aminotransaminase and leukocyte count decreased significantly (mean difference -35 ± 17 U/L, P = .049 and -3.8 ± 1.7*10E9/L, P = .028, respectively), whereas albumin level increased significantly (mean difference 2.1 ± 0.9 g/L, P = .027). Alanine aminotransaminase showed a nonsignificant reduction (mean difference -30 ± 22 U/L, P = .194). In 11 patients, the lipid emulsion was reintroduced, after which triglyceride levels showed a significant increase (mean difference 1.5 ± 0.30 mmol/L, P = .001). Short-term withdrawal of the lipid fraction in the PN mixture is associated with a significant reduction of plasma triglyceride concentration. Reintroduction was related to an increase of triglyceride concentration. In addition, liver enzyme abnormalities and leukocyte count reduced, whereas albumin levels increased, suggesting that even short withdrawal of the lipid emulsion diminished hepatocellular damage and systemic inflammation.

Heparin Treatment for Severe Hypertriglyceridemia in Diabetic Ketoacidosis

In a patient with diabetic ketoacidosis complicated by severe elevation of plasma triglyceride concentrations, treatment with low-level intravenous unfractionated heparin led to prompt reduction in plasma triglyceride concentration and may have prevented the development of hypertriglyceridemia-associated acute pancreatitis. This article reviews the rationale for this treatment and surveys prior publications using heparin in this and similar settings.

Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin.

Leptin is an adipocyte-derived circulating satiety factor with a variety of biological effects. Evidence has accumulated suggesting that leptin may modulate glucose and lipid metabolism. In the present study, we examined lipid metabolism in transgenic skinny mice with elevated plasma leptin concentrations. The plasma concentrations of triglycerides and free fatty acids in transgenic skinny mice were 71.5 (P < 0.01) and 89.1% (P < 0.05) of those in their nontransgenic littermates, respectively. Separation of plasma into lipoprotein classes by ultracentrifugation revealed that very low density lipoprotein-triglyceride concentrations were markedly reduced in transgenic skinny mice relative to the controls. The clearance of triglycerides estimated by a fat-loading test was enhanced in transgenic skinny mice; the triglyceride concentration in transgenic skinny mice 3 h after fat loading was 39.7% (P < 0.05) of that of their nontransgenic littermates. Postheparin plasma lipoprotein lipase activity increased 1.4-fold (P < 0.05) in transgenic skinny mice. Our data demonstrated a significant reduction in plasma triglyceride concentrations, accompanied by increased lipoprotein lipase activity in transgenic skinny mice overexpressing leptin, suggesting that leptin plays a role in long-term triglyceride metabolism.

Cardiovascular disease in the JCR:LA-cp rat.

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+) are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of alpha-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.

Prolonged inhibition of platelet aggregation after n-3 fatty acid ethyl ester ingestion by healthy volunteers

This study addressed two questions: 1) whether a relatively low dose of n-3 fatty acid ethyl esters (n-3 FAs) administered to healthy volunteers for a prolonged period of time would exert beneficial effects on plasma lipids, platelet function, and thromboxane biosynthesis; and 2) whether a short-term loading treatment (6 wk) with 6 g n-3 FAs/d followed by 12 wk with 3 g/d results in more pronounced effects. After 6 wk treatment a reduction of plasma triglyceride concentration and an accumulation of EPA and DHA in plasma were observed. A longer period of treatment with n-3 FAs was necessary to affect platelet aggregation and thromboxane A2 biosynthesis. At 12 and 18 wk, platelet aggregation, thromboxane A2 formation, and the excretion of thromboxane metabolites in urine were reduced, particularly in subjects who received 6 g n-3 FAs/d during the initial 6 wk. After treatment ended, triglyceride and thromboxane A2 biosynthesis returned to baseline values within 4 wk, whereas platelet aggregation remained impaired for > or = 14 wk. The longlasting impairment in platelet aggregation was accompanied by the retention of n-3 FAs in platelet phospholipids.

Postheparin lipolytic activity and plasma lipoprotein response to ω-3 polyunsaturated fatty acids in patients with primary hypertriglyceridemia

The hypotriglyceridemic action of omega-3 (n-3) fatty acids is attributed primarily to reduction in hepatic triglyceride synthesis and reduced secretion of very-low-density lipoproteins (VLDLs). However, increased catabolism of triglyceride-rich lipoproteins was reported and could be due to increased availability of peripheral lipoprotein lipase (LPL) or hepatic lipase (HL). In this study plasma lipoproteins and postheparin activities of LPL and HL were determined in 12 patients with primary hypertriglyceridemia before and during isocaloric substitution of omega-3 fatty acids (10 g/d) for 4 wk. Omega-3 polyunsaturates resulted in 53% and 61% reductions in plasma triglyceride and VLDL-cholesterol concentrations, respectively (P less than 0.0001). However, low-density-lipoprotein (LDL)-cholesterol concentrations increased by 26% (P less than 0.001). Activities of postheparin LPL and HL essentially remained the same. Thus, in patients with primary hypertriglyceridemia, reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.

Long-term effects of bezafibrate on in vivo VLDL-triglyceride production in the rat

Long-term effects of bezafibrate on in vivo production of VLDL-triglyceride were studied in the rat. Bezafibrate given at a daily dose of 30 mg/kg body weight for 14 days produced a decrease not only in triglyceride by 51% but in cholesterol by 28% and phospholipid by 18%. Despite a marked reduction in plasma triglyceride concentrations, there was no significant change in the rate of VLDL-triglyceride secretion from the liver into the circulation between bezafibrate-treated and control animals (1113 ± 58 and 1234 ± 63 μg/min, respectively). In addition, bezafibrate produced no change in lipid composition in VLDL. These results suggest that bezafibrate enhances triglyceride removal from the circulation, which leads to reduction in plasma triglyceride.

The use of diet to lower plasma cholesterol levels.

The basic principle of a lipid lowering diet is restriction of saturated fat intake. This can be achieved by reducing the consumption of dairy products and fats of animal origin. To keep energy intake constant (in normal weight individuals) complex carbohydrate or unsaturated fat is substituted for saturated fat. Diets with various proportions of complex carbohydrate, monounsaturated fatty acids, and polyunsaturated fatty acids have been proposed. In theory, the latter should be the best substitute for saturated fatty acids in a lipid lowering diet. Polyunsaturated fat has cholesterol lowering activity that is additive to the effect obtained by reducing the amount of dietary saturated fat. In practice, either polyunsaturated fatty acids or monounsaturated fatty acids or complex carbohydrate exert very similar effects on plasma cholesterol levels when substituted for saturated fatty acids in a lipid lowering diet. Their effects on plasma triglyceride are, however, dissimilar. Increased consumption of polyunsaturated fat leads to pronounced reduction in plasma triglyceride concentrations. Conversely, a high carbohydrate diet has a hypertriglyceridemic effect that is more pronounced in individuals with diabetes or preexisting hypertriglyceridemia. Dietary cholesterol should also be reduced in order to lower plasma cholesterol levels. However, the hypocholesterolemic effect of this measure has a large interindividual variation which is further influenced by the fat composition of the diet. Dietary fibre has received attention in more recent years for its ability to reduce plasma cholesterol levels. Fibre rich foods are not equally effective in this respect, the most active being legumes, fruit and vegetables. When high carbohydrate-high fibre diets are consumed, the hypertriglyceridaemic effect of carbohydrate is counteracted by dietary fibre.(ABSTRACT TRUNCATED AT 250 WORDS)

Chylomicrons from patients with Type V hyperlipoproteinemia inhibit platelet function

Platelet aggregation and [ 14C]serotonin release induced by collagen and also by ADP and thrombin were significantly decreased in patients with primary Type V hyperlipoproteinemia. Platelets derived from these patients lost their hyporesponsiveness to thrombin and ADP (but not to collagen) after washings and isolation from their plasma environment. On incubation of platelets derived from normolipidemic controls with plasma derived from patients, platelet aggregation and [ 14C]serotonin release were lowered by 20% and 30%, respectively. On incubation of these platelets with 100 mg/dl of chylomicron triglyceride, a 40% reduction in both platelet aggregation and [ 14C]serotonin release was observed. The inhibition of platelet activity was positively correlated with chylomicron concentration up to a concentration of 225 mg/dl by chylomicron triglyceride. In 2 patients, bezafibrate administration (600 mg/day) resulted in marked reduction of plasma triglyceride concentration and a parallel improvement in platelet function. The platelet hyporesponsiveness in patients with Type V hyperlipoproteinemia appears to be a consequence of platelet-chylomicron interaction. This depressed platelet function may be responsible for the absence of overt atherosclerosis noted in these patients.

Studies on the regulation of insulin binding by liver plasma membranes from Zucker fatty rats.

The hyperinsulinemia of obese rodents has been associated with a reduced number of hepatic insulin receptors except in hepatocytes from fatty Zucker rats. We isolated liver plasma membranes from 10-11-wk-old lean and fatty Zucker rats, some of which were injected with streptozotocin 2--4 wk earlier. We have determined that although the number of hepatic insulin receptors is not reduced in young hyperinsulinemic fatty Zucker rats, the number of receptors can be increased when the hyperinsulinemia of the fatty rats is reduced by treatment with streptozotocin. In the fatty rats, this reduction in circulating insulin is accompanied by a reduction in plasma triglyceride concentration, consistent with a decreased stimulation of hepatic lipogenesis. Competitive binding curves for insulin were obtained with isolated liver plasma membranes and 125I-insulin. Analysis of these curves for affinity and number of receptors indicated that the number of insulin receptors was unchanged for the fatty control rats relative to the lean control rats but was increased in streptozotocin-treated animals. These data indicate that the regulation of hepatic insulin receptors is altered in the young fatty Zucker rat as characterized by a lack of downregulation of hepatic insulin receptors by hyperinsulinemia and an upregulation of hepatic insulin receptors at insulin concentrations higher than those found in lean rats. An altered state of hepatic insulin receptor regulation may be characteristic of developing obesity.

Rat plasma lipoproteins and apolipoproteins in experimental hypothyroidism.

Hyperlipidemia associated with hypothyroidism is well documented in man and several animal species. The effect of hypothyroidism on apolipoprotein metabolism in the absence of complicating factors such as high cholesterol or fat content in the diet is virtually unknown. Hypothyroidism was therefore induced in male Sprague-Dawley rats by radiothyroidectomy (RTx-treated) or treatment with propylthiouracil (PTU-treated). Both treatments resulted in an over 90% decrease in circulating thyroid hormone concentrations accompanied by a 50-100% increase in plasma cholesterol and a 20-40% reduction in plasma triglyceride concentrations. Plasma apo E and apo B concentrations increased by 100% in the PTU-treated group and 40-50% in the RTx-group. Apo A-I increased 10 and 30% in the RTx- and PTU-treated rats, respectively, while the concentration of apo A-IV was not altered. A large increase in the low-density (LDL) and high-density lipoprotein (HDL) protein was observed and accompanied by a marked reduction of very low density lipoprotein (VLDL) in the hypothyroid rats. The electrophoretic pattern of plasma lipoproteins in the hypothyroid rats was changed by the appearance of a slow pre-beta band shown to be beta-VLDL. A redistribution of apo B occurred within the lipoprotein fractions. Apo B content in the VLDL fraction decreased and a large increase was noted in LDL. The major portion of the apo E and apo A-I increment was recovered in the HDL and to a lesser degree in LDL. An accumulation of apo E-rich larger HDL particles, resembling HDLc in apolipoprotein composition and distinct from the apo A-I-containing species, was observed by column chromatography. The results presented are consistent with the hypothesis that hypothyroidism in the rat may induce an accelerated production of VLDL catabolic remnants, including LDL, but at the same time reduce the rate of removal of these lipoproteins from the circulation.

The effects of altered thyroid status on lipid metabolism in the genetic hyperlipemic zucker rat

Exposure to thyroid hormone (T 4) has been known to affect the plasma triglyceride (TG) as well as the plasma cholesterol level, but the mechanisms and degree of response in genetic hyperlipidemic states have not been defined. In the present study, we examined TG secretion and removal in vivo in genetically hyperlipemic Zucker rats maintained in hypothyroid, euthyroid, and hyperthyroid states for 6 weeks. The induction of the hypothyroid state resulted in marked weight loss with reduced food intake, and a parallel reduction in plasma TG concentration, hepatic TG production, and peripheral TG removal. In contrast, a similar degree of weight loss in the hyperthyroid state was associated with increased food intake, but no significant reduction in plasma TG concentration, production, or clearance. The changes in plasma cholesterol concentration in the hyperthyroid state were striking, with a 94% reduction in LDL cholesterol, but only a minimal reduction in the HDL cholesterol level. The hypothyroid state was not associated with significant changes in the pre-existing hypercholesterolemic state in the Zucker rat. The results suggest that the very low density lipoprotein TG metabolism is influenced by hypothyroid but not the hyperthyroid state in this model of human genetic Type IV hyperlipemia. The primary reduction in LDL relative to HDL in response to thyroxine excess, suggests a therapeutic potential in disorders of genetic hyperlipidemia.

Pancreatic alpha and beta cell function in familial dysbetalipoproteinemia.

Resistance to both insulin and glucagon have been considered as possible causes of primary hypertriglyceridemia. In the present research, we have compared insulin and glucagon secretion in five hyperlipidemic patients with familial dysbetalipoproteinemia with five normolipidemic control subjects matched for age, sex and adiposioty. Plasma insulin and glucagon concentrations mesaured during standard oral glucose tolerance and arginine infusion tests were similar in the two groups. Blood glucose fell transiently in the controls, but not in the patients, during the Himsworth test (100 g glucose orally plus 0.05 U insulin per kg body weight intravenously). There were no significant differences in plasma FFA concentrations and responses during all tests between the groups. The percentage reduction in plasma triglyceride concentration during infusion of arginine was similar in the two groups. These results suggest that the patients with familial dysbetalipoproteinemia were slightly less insulin sensitive than the controls. However, primary insensitivity to glucagon or insulin does not appear to be fundamental to the pathogenesis of hyperlipidemia in familial dysbetalipoproteinemia.

Reduction of plasma triglyceride concentration by acute stress in man

Three different forms of stress all resulted in acute reduction of plasma triglyceride concentrations. Pyrogen reactions in two hypertriglyceridemic men resulted in the lowering of very-low-density lipoprotein (VLDL) triglyceride levels by 93% and 73% due to decreased secretion of this lipoprotein into plasma. More modest reductions in plasma triglycerides were observed after 2-deoxyglucose-induced intracellular glucopenia and insulin-induced hypoglycemia. With hypoglycemia, the lowering of plasma triglyceride concentration correlated significantly with the stimulation of urinary epinephrine output ( r = 0.86) but with neither the urinary norepinephrine response nor with the increase in plasma immunoreactive glucagon levels. To further test whether these changes in plasma triglyceride levels were mediated via the sympathetic nervous system, hypoglycemia was evoked by insulin in subjects with traumatic spinal cord transections. Two such subjects, who demonstrated sympathetic stimulation in response to hypoglycemia, had evidence of reduced VLDL secretion into plasma, while in two who had no evidence of an adrenergic response, VLDL secretion was not inhibited. Thus, acute lowering of plasma triglyceride concentrations by certain forms of stress appears to be mediated via the sympathetic nervous system.