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Biomedical subjects

Gary F Lewis

Publications and source records attributed to Gary F Lewis.

36 records · Page 2Linked to original sources
PubMed2004

Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone.

Postheparin plasma hepatic lipase (HL) activity has been shown to correlate with features of the metabolic syndrome and type 2 diabetes in humans. We examined HL postheparin plasma enzyme activity, hepatocyte mRNA, and protein mass in the insulin-resistant, fructose-fed Syrian golden hamster, and the response of the insulin-sensitizing peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Male Syrian golden hamsters were treated for 5 weeks with 1) normal diet (DIET group), 2) 60% fructose diet (FRUC group), or 3) 60% fructose and rosiglitazone (20 mmol . kg(-1) . day(-1)) (FRUC+RSG group). Hepatocyte HL mRNA, protein mass, and postheparin plasma HL activity were increased in FRUC compared with DIET hamsters. FRUC+RSG hamsters had partial normalization of HL mRNA, mass, and activity. There was a shift in the size of LDL particles from large to small in FRUC animals and a shift back to large LDL size in FRUC+RSG. This is the first demonstration that HL hepatocyte mRNA, mass, and plasma enzymatic activity increase concomitantly with induction of an insulin-resistant state and can be partially normalized by treatment with an insulin sensitizer. The increase in HL in insulin-resistant states may play an important role in the typical dyslipidemia of these conditions, and reduction of HL could explain some of the beneficial effects of insulin sensitizers on the plasma lipid profile.

Animals↗
PubMed2004

Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies.

Protein tyrosine phosphatase-1B (PTP-1B) plays an important role in regulation of insulin signal transduction, and modulation of PTP-1B expression seems to have a profound effect on insulin sensitivity and diet-induced weight gain. The molecular link between PTP-1B expression and metabolic dyslipidemia, a major complication of insulin resistance, was investigated in the present study using PTP-1B knockout mice as well as overexpression and suppression of PTP-1B. Chronic fructose feeding resulted in a significant increase in plasma VLDL in wild-type mice but not in PTP-1B knockout mice. Lipoprotein profile analysis of plasma from PTP-1B knockout mice revealed a significant reduction in apolipoprotein B (apoB100) lipoproteins, associated with reduced hepatic apoB100 secretion from isolated primary hepatocytes. In addition, treatment of cultured hepatoma cells with PTP-1B siRNA reduced PTP-1B mass by an average of 41% and was associated with a 53% decrease in secretion of metabolically labeled apoB100. Conversely, adenoviral-mediated overexpression of PTP-1B in HepG2 cells downregulated the phosphorylation of insulin receptor and insulin receptor substrate-1 and caused increases in cellular and secreted apoB100 as a result of increased intracellular apoB100 stability. Collectively, these findings suggest that PTP-1B expression level is a key determinant of hepatic lipoprotein secretion, and its overexpression in the liver can be sufficient to induce VLDL overproduction and the transition to a metabolic dyslipidemic state.

Animals↗
PubMed2003

Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I.

BACKGROUND: We have shown previously that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, contributes to HDL lowering in humans by enhancing the clearance of HDL apolipoprotein (apo) A-I from the circulation. In the New Zealand White rabbit, an animal naturally deficient in hepatic lipase (HL), we demonstrated that TG enrichment of HDL per se is not sufficient to enhance HDL clearance in the absence of ex vivo lipolysis by HL. Here, we examined in the rabbit the interaction between in vivo HL lipolytic action and HDL TG enrichment on the subsequent metabolic clearance of HDL apoA-I. METHODS AND RESULTS: The clearance of HDL, TG-enriched with human VLDL (12% mass TG), was compared with a simultaneously injected native rabbit HDL tracer (8% TG) 5 to 7 days after injection of recombinant (r) adenovirus expressing either the human HL or lacZ transgene (n=6 animals each). In rHL-Adv rabbits, HL activity levels were 2- to 7-fold higher (versus rlacZ-Adv controls; P<0.01), and there were significant (P<0.05) reductions in HDL TG (-18%), cholesterol (-21%), cholesteryl ester (-24%), and phospholipid (-14%). Moreover, the clearance of TG-enriched versus native HDL was significantly greater (by 50%; 0.122+/-0.022 versus 0.081+/-0.015 pools/h; P<0.01) in rHL-Adv rabbits but not in controls. CONCLUSIONS: These studies have shown that TG enrichment of HDL in the presence but not in the absence of in vivo expression of moderate levels of lipolytically active HL results in enhanced HDL clearance, demonstrating the important interaction between TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.

Adenoviridae↗
PubMed2003

Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensin II type I receptor blocker.

BACKGROUND: ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated. METHODS AND RESULTS: We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35+/-5 versus 54+/-4 mmol x kg(-1) x min(-1), P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73+/-11% versus 27+/-18%, P<0.05), and greater glucose disposal at high-dose insulin (135+/-5 versus 92+/-4 mmol x kg(-1) x min(-1), P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B2 receptor antagonist) and NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium. CONCLUSIONS: OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B2 receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Angiotensin Receptor Antagonists↗
PubMed2003

Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity.

Hypertriglyceridemia, low plasma concentrations of high density lipoproteins (HDL) and qualitative changes in low density lipoproteins (LDL) comprise the typical dyslipidemia of insulin resistant states and type 2 diabetes. Although isolated low plasma HDL-cholesterol (HDL-c) and apolipoprotein A-I (apo A-I, the major apolipoprotein component of HDL) can occur in the absence of hypertriglyceridemia or any other features of insulin resistance, the majority of cases in which HDL-c is low are closely linked with other clinical features of insulin resistance and hypertriglyceridemia. We and others have postulated that triglyceride enrichment of HDL particles secondary to enhanced CETP-mediated exchange of triglycerides and cholesteryl ester between HDL and triglyceride-rich lipoproteins, combined with the lipolytic action of hepatic lipase (HL), are driving forces in the reduction of plasma HDL-c and apoA-I plasma concentrations. The present review focuses on these metabolic alterations in insulin resistant states and their important contributions to the reduction of HDL-c and HDL-apoA-I plasma concentrations.

Animals↗
PubMed2003

Mechanisms of the free fatty acid-induced increase in hepatic glucose production.

The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia.

Animals↗
PubMed2003

Free fatty acid-mediated impairment of glucose-stimulated insulin secretion in nondiabetic Oji-Cree individuals from the Sandy Lake community of Ontario, Canada: a population at very high risk for developing type 2 diabetes.

The Oji-Cree population of the Sandy Lake region of Ontario, Canada, has the third highest prevalence of type 2 diabetes in the world. Changes in their diet and physical activity over the past half-century, particularly the marked increase in consumption of dietary fats, are felt to be important factors accounting for this epidemic. The aim of the present study was to examine the beta-cell response to a 48-h approximately twofold elevation of plasma free fatty acids (FFAs) (induced by Intralipid and heparin infusion) in members of the Sandy Lake Oji-Cree population (n = 12) and to compare the response to that in healthy age-matched nondiabetic Caucasian subjects (n = 16). The insulin secretion rate, insulin sensitivity index (S(I)), and disposition index (D(I)) (an index of insulin secretion that takes into account the ambient S(I)) were assessed in response to a 4-h graded intravenous glucose infusion followed by a 20 mmol/l 2-h hyperglycemic clamp. Total insulin secretory response to the graded glucose infusion did not change after a 48-h FFA elevation versus saline control in Caucasians and increased by approximately 30% in Oji-Cree individuals (P = 0.04 for difference between the two groups). Infusion of heparin-Intralipid reduced S(I) by approximately 40% in both groups (P = 0.002). Although D(I) was markedly reduced by heparin-Intralipid infusion in Caucasians (by approximately 40%), it was reduced by only 15% in Oji-Cree individuals (P = 0.03 for difference of response between the two groups). However, S(I) and D(I) in the Oji-Cree individuals were already much lower than in Caucasians at baseline, in keeping with the very high risk of type 2 diabetes in this population. It is concluded that Oji-Cree individuals from a community at very high risk for developing type 2 diabetes are not more susceptible to the FFA-induced desensitization of glucose-stimulated insulin secretion than healthy non-Natives and, in fact, appear to be less susceptible. Whether this reflects an inherent resistance to lipotoxicity or an already-present lipotoxic effect in this population will require further study.

Blood Glucose↗
PubMed2002

Effect of atorvastatin on high-density lipoprotein apolipoprotein A-I production and clearance in the New Zealand white rabbit.

BACKGROUND: HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans. Whether atorvastatin-mediated alterations in HDL turnover in vivo contribute to this effect has not previously been investigated. We therefore studied the effect of atorvastatin on HDL apolipoprotein (apo) A-I production and clearance in normolipidemic male New Zealand White rabbits. METHODS AND RESULTS: Kinetic studies of HDL-apoA-I radiolabeled with 131I were performed in chow-fed rabbits after 3 weeks of atorvastatin treatment of 5 mg x kg(-1) x d(-1) (n=7) versus placebo-treated rabbits (n=7). Our results showed a significantly (P<0.001) more rapid clearance ( approximately 2-fold) of HDL apoA-I in atorvastatin-treated animals compared with the control group (0.121+/-0.012 versus 0.061+/-0.004 pools/h, respectively), accompanied by a lesser 48% increase in the apoA-I production rate (3.84+/-0.38 versus 2.59+/-0.41 mg x kg(-1) x h(-1), P=0.06). Accordingly, plasma apoA-I levels in atorvastatin-treated animals declined significantly (P<0.05, n=8 animals) after 3 weeks of treatment (173.5+/-1.8 mg/dL) from baseline values. CONCLUSIONS: These data suggest that the effect on apoA-I levels observed with atorvastatin at higher drug doses in humans may be caused at least in part by enhanced HDL apoA-I catabolism, which is not entirely offset by a concomitant increase in apoA-I production. Whether this finding results from an effect of atorvastatin on HDL particle composition or on receptors involved in circulating HDL holoparticle clearance will require further study.

Animals↗
PubMed2002

Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction.

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.

Acetates↗
PubMed2002

Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster.

To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulin-mediated suppression of the glucose production rate and to a approximately 2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a approximately 50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed + rosiglitazone-treated) versus F (fructose-fed + placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.

Animal Nutritional Physiological Phenomena↗
PubMed2002

Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation.

The precise biochemical mechanisms underlying the reduction of HDL levels in hypertriglyceridemic states are currently not known. In humans, we showed that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, enhances the clearance of HDL-associated apolipoprotein A-I (apoA-I) from the circulation. In the New Zealand White rabbit (an animal model naturally deficient in hepatic lipase [HL]), however, TG enrichment of HDL is not sufficient to alter the clearance of either the protein or lipid moieties of HDL. In the present study, therefore, we determined in the New Zealand White rabbit the combined effects of ex vivo TG enrichment and lipolytic transformation of HDL by HL on the subsequent metabolic clearance of HDL apoA-I. Results of the in vivo kinetic studies (n=18 animals) showed that apoA-I associated with TG-enriched rabbit HDL modified ex vivo by catalytically active HL was cleared 22% more rapidly versus TG-enriched HDL incubated with heat-inactivated HL, and 26% more rapidly than fasting (TG-poor) HDL incubated with active HL (P<0.05 for both). Furthermore, a strong correlation was observed between the HDL TG content and apoA-I fractional catabolic rate (0.59, P<0.05) in the combined active HL groups. These data establish that TG enrichment of HDL with subsequent lipolysis by HL enhances HDL apoA-I clearance, but neither TG enrichment of HDL without HL lipolysis nor HL lipolysis in the absence of previous TG enrichment of HDL is sufficient to enhance HDL clearance. These data further support the important interaction between HDL TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.

Animals↗
PubMed2002

Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.

The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.

Animals↗
PubMed2002

Sensitivity to acute insulin-mediated suppression of plasma free fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans.

One important mechanism whereby obesity-associated insulin resistance leads to VLDL overproduction is thought to be by the increased flux of free fatty acids (FFAs) from extrahepatic tissues to liver, which arises as a direct consequence of impaired insulin action in adipose tissue and skeletal muscle. The aim of the present study was to address whether direct measures of peripheral tissue insulin sensitivity with regard to FFAs and glucose in the fasting state are good predictors of postabsorptive VLDL triglyceride secretion rate (VLDL-TG ASR) in humans, independent of obesity. Eighteen healthy control subjects, after an overnight fast, underwent three studies 3 weeks apart, in random order. Study 1: VLDL-TG levels, fractional clearance rate (per h), and VLDL-TG ASR were determined after an intravenous bolus of [1,1,2,3,3-(2)H(5)] glycerol. Study 2: Insulin sensitivity (S(I)), acute insulin response (AIR), and acute C-peptide response to glucose were assessed by frequently sampled intravenous glucose tolerance test using the minimal model approach. Study 3: Insulin-mediated suppression of plasma FFAs (k) and insulin clearance were assessed in response to a low-dose stepwise intravenous insulin infusion. BMI (R(2) = 0.54), AIR, and fasting insulin levels were positively and S(I) negatively correlated with VLDL-TG ASR, but there was no significant association with plasma FFAs or k. Only BMI remained significantly associated with VLDL-TG ASR in multivariate analysis. The best multivariate model for VLDL-TG ASR (R(2) = 0.61, P = 0.0008) included BMI (P = 0.0008) and S(I) (P = 0.12, inversely correlated). VLDL-TG secretion is predicted by BMI, independently of direct measures of insulin sensitivity. The sensitivity to insulin's acute suppressive effect on plasma FFA levels during fasting is not an important determinant of postabsorptive VLDL-TG secretion in humans.

Adolescent↗
PubMed2001

Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance.

A fructose-fed hamster model of insulin resistance was previously documented to exhibit marked hepatic very low density lipoprotein (VLDL) overproduction. Here, we investigated whether VLDL overproduction was associated with down-regulation of hepatic insulin signaling and insulin resistance. Hepatocytes isolated from fructose-fed hamsters exhibited significantly reduced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2. Phosphatidylinositol 3-kinase activity as well as insulin-stimulated Akt-Ser473 and Akt-Thr308 phosphorylation were also significantly reduced with fructose feeding. Interestingly, the protein mass and activity of protein-tyrosine phosphatase-1B (PTP-1B) were significantly higher in fructose-fed hamster hepatocytes. Chronic ex vivo exposure of control hamster hepatocytes to high insulin also appeared to attenuate insulin signaling and increase PTP-1B. Elevation in PTP-1B coincided with marked suppression of ER-60, a cysteine protease postulated to play a role in intracellular apoB degradation, and an increase in the synthesis and secretion of apoB. Sodium orthovanadate, a general phosphatase inhibitor, partially restored insulin receptor phosphorylation and significantly reduced apoB secretion. In summary, we hypothesize that fructose feeding induces hepatic insulin resistance at least in part via an increase in expression of PTP-1B. Induction of hepatic insulin resistance may then contribute to reduced apoB degradation and enhanced VLDL particle assembly and secretion.

Animals↗
PubMedDate not supplied

The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states.

Hypertriglyceridemia and reduced plasma levels of high-density lipoprotein cholesterol (HDL-c) are the most frequent forms of dyslipidemia observed in insulin-resistant states, such as obesity, impaired fasting glucose, and Type 2 diabetes, and are highly atherogenic in these settings. The hypertriglyceridemia of insulin resistance is primarily due to an overproduction of very low-density lipoproteins (VLDL), and in some instances, is also due to reduced VLDL clearance and postprandial accumulation of VLDL, chylomicrons, and their remnants [i.e., triglyceride (TG)-rich lipoproteins]. TG-rich lipoproteins actively exchange their core lipids with HDL in vivo, a process that is facilitated by cholesteryl ester (CE) transfer protein (CETP), and in hypertriglyceridemic states, this process is enhanced. This results in TG enrichment of HDL in hypertriglyceridemic states. There is accumulating evidence that TG enrichment of HDL plays an important role in determining the rate at which HDL particles are cleared from the circulation. Here, we review the evidence that TG-enriched HDL, when modulated by lipolytic enzymes in the circulation, are catabolized more rapidly than native HDL, and may ultimately explain the lowering of HDL-c in insulin-resistant, hypertriglyceridemic states. Since we have recently reviewed in detail the evidence by Lamarche et al. [Clin. Chim. Acta 286 (1999) 145; J. Clin. Invest. 103 (8) (1999) 1191.] to support this hypothesis, in the present brief review, we will focus predominantly on our own recent research in this area.

Cholesterol, HDL↗