Ira J. Goldberg

Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic–euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle–lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver–lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.

Lipoprotein lipase genetics, lipid uptake, and regulation

Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3) LPL gene regulation: the LPL promoter and its regulatory elements are described.

Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.

Previous data suggest that apolipoprotein (apo) CIII may inhibit both triglyceride hydrolysis by lipoprotein lipase (LPL) and apo E-mediated uptake of triglyceride-rich lipoproteins by the liver. We studied apo B metabolism in very low density (VLDL), intermediate density (IDL), and low density lipoproteins (LDL) in two sisters with apo CIII-apo AI deficiency. The subjects had reduced levels of VLDL triglyceride, normal LDL cholesterol, and near absence of high density lipoprotein (HDL) cholesterol. Compartmental analysis of the kinetics of apo B metabolism after injection of 125I-VLDL and 131I-LDL revealed fractional catabolic rates (FCR) for VLDL apo B that were six to seven times faster than normal. Simultaneous injection of [3H]glycerol demonstrated rapid catabolism of VLDL triglyceride. VLDL apo B was rapidly and efficiently converted to IDL and LDL. The FCR for LDL apo B was normal. In vitro experiments indicated that, although sera from the apo CIII-apo-AI deficient patients were able to normally activate purified LPL, increasing volumes of these sera did not result in the progressive inhibition of LPL activity demonstrable with normal sera. Addition of purified apo CIII to the deficient sera resulted in 20-50% reductions in maximal LPL activity compared with levels of activity attained with the same volumes of the native, deficient sera. These in vitro studies, together with the in vivo results, indicate that in normal subjects apo CIII can inhibit the catabolism of triglyceride-rich lipoproteins by lipoprotein lipase.

Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy

Lipoprotein lipase is the principal enzyme that hydrolyzes circulating triglycerides and liberates free fatty acids that can be used as energy by cardiac muscle. Although lipoprotein lipase is expressed by and is found on the surface of cardiomyocytes, its transfer to the luminal surface of endothelial cells is thought to be required for lipoprotein lipase actions. To study whether nontransferable lipoprotein lipase has physiological actions, we placed an alpha-myosin heavy-chain promoter upstream of a human lipoprotein lipase minigene construct with a glycosylphosphatidylinositol anchoring sequence on the carboxyl terminal region. Hearts of transgenic mice expressed the altered lipoprotein lipase, and the protein localized to the surface of cardiomyocytes. Hearts, but not postheparin plasma, of these mice contained human lipoprotein lipase activity. More lipid accumulated in hearts expressing the transgene; the myocytes were enlarged and exhibited abnormal architecture. Hearts of transgenic mice were dilated, and left ventricular systolic function was impaired. Thus, lipoprotein lipase expressed on the surface of cardiomyocytes can increase lipid uptake and produce cardiomyopathy.

AHA Dietary Guidelines Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association

This document presents guidelines for reducing the risk of cardiovascular disease by dietary and other lifestyle practices. Since the previous publication of these guidelines by the American Heart Association,1 the overall approach has been modified to emphasize their relation to specific goals that the AHA considers of greatest importance for lowering the risk of heart disease and stroke. The revised guidelines place increased emphasis on foods and an overall eating pattern and the need for all Americans to achieve and maintain a healthy body weight (Table⇓). View this table: Table 1. Summary of Dietary Guidelines The major guidelines are designed for the general population and collectively replace the “Step 1” designation used for earlier AHA population-wide dietary recommendations. More individualized approaches involving medical nutrition therapy for specific subgroups (for example, those with lipid disorders, diabetes, and preexisting cardiovascular disease) replace the previous “Step 2” diet for higher-risk individuals. The major emphasis for weight management should be on avoidance of excess total energy intake and a regular pattern of physical activity. Fat intake of ≤30% of total energy is recommended to assist in limiting consumption of total energy as well as saturated fat. The guidelines continue to advocate a population-wide limitation of dietary saturated fat to <10% of energy and cholesterol to <300 mg/d. Specific intakes for individuals should be based on cholesterol and lipoprotein levels and the presence of existing heart disease, diabetes, and other risk factors. Because of increased evidence for the cardiovascular benefits of fish (particularly fatty fish), consumption of at least 2 fish servings per week is now recommended. Finally, recent studies support a major benefit on blood pressure of consuming vegetables, fruits, and low-fat dairy products, as well as limiting salt intake (<6 grams per day) and alcohol (no more than 2 drinks per day for men and …

Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.

OBJECTIVE The aim was to develop clinical practice guidelines on hypertriglyceridemia. PARTICIPANTS The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. CONSENSUS PROCESS Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequentially by The Endocrine Societys CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150-999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of > 1000 mg/dl) be considered a risk for pancreatitis. The Task Force also recommends that patients with hypertriglyceridemia be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease. The Task Force recommends that the treatment goal in patients with moderate hypertriglyceridemia be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate should be used as a first-line agent.

Wine and Your Heart A Science Advisory for Healthcare Professionals From the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association

Data regarding the incidence of coronary heart disease (CHD) in different populations have generated a series of hypotheses that protective substances in the diet may counteract the harmful effects of high-cholesterol, high-saturated-fat diets. One such potential food substance is wine, especially red wine. The purpose of this advisory is to summarize the current literature on wine intake and cardiovascular disease. As stated in a previous advisory on alcohol and CHD,1 recommendations for use of a nonessential dietary component with significant health hazards require definitive evidence of benefit. Although population surveys and in vitro experiments show that wine may have limited beneficial effects, more compelling data exist for other less-hazardous approaches to cardiovascular risk reduction. ### Do Epidemiological Data Support a Role for Alcoholic Beverages (Wine in Particular) as a Cardioprotective Substance? There are more than 60 prospective studies that suggest an inverse relation between moderate alcoholic beverage consumption and CHD.2 A consistent coronary protective effect has been observed for consumption of 1 to 2 drinks per day of an alcohol-containing beverage; however, higher intakes are associated with increased total mortality.3 4 Although ecological studies support an association between wine intake and lower CHD risk, these studies are confounded by lifestyle, diet, and other cultural factors.4 5 6 7 Most cohort studies do not support an association between type of alcoholic beverage and prevention of heart disease; however, a few have suggested that wine may be more beneficial than beer or spirits.8 9 It remains unclear whether red wine confers any advantage over white wine or other types of alcoholic beverages. A synthesis of the observational studies is difficult because of wide variations in methodology, measurement error in alcohol consumption, and biological variability in response to alcohol consumption (which tends to underestimate effect). Moreover, consumption may vary over time, and this is often not taken into consideration in observational studies. Consumption of alcohol …

Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice

Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

Lipoprotein Metabolism during Acute Inhibition of Hepatic Triglyceride Lipase in the Cynomolgus Monkey

The role of the enzyme hepatic triglyceride lipase was investigated in a primate model, the cynomolgus monkey. Antisera produced against human postheparin hepatic lipase fully inhibited cynomolgus monkey posttheparin plasma hepatic triglyceride lipase activity. Lipoprotein lipase activity was not inhibited by this antisera. Hepatic triglyceride lipase activity in liver biopsies was decreased by 65-90% after intravenous infusion of this antisera into the cynomolgus monkey. After a 3-h infusion of the antisera, analytic ultracentrifugation revealed an increase in mass of very low density lipoproteins (S(f) 20-400). Very low density lipoprotein triglyceride isolated by isopycnic ultracentrifugation increased by 60-300%. Analytic ultracentrifugation revealed an increase in mass of lipoproteins with flotation greater than S(f) 9 (n = 4). The total mass of intermediate density lipoproteins (S(f) 12-20) approximately doubled during the 3 h of in vivo enzyme inhibition. While more rapidly floating low density lipoproteins (S(f) 9-12) increased, the total mass of low density lipoproteins decreased after infusion of the antibodies. The changes in high density lipoproteins did not differ from those in control experiments. In order to determine whether the increases of plasma concentrations of very low density lipoproteins were due to an increase in the rate of synthesis or a decrease in the rate of clearance of these particles, the metabolism of radiolabeled homologous very low density lipoproteins was studied during intravenous infusion of immunoglobulin G prepared from the antisera against hepatic triglyceride lipase (n = 3) or preimmune goat sera (n = 3). Studies performed in the same animals during saline infusion were used as controls for each immunoglobulin infusion. There was a twofold increase in the apparent half-life of the very low density lipoprotein apolipoprotein-B tracer in animals receiving the antibody, consistent with a decreased catabolism of very low density lipoproteins. Concomitantly, the rise in low density lipoprotein apoprotein-B specific activity was markedly delayed. None of these changes were observed during infusion of preimmune immunoglobulin G.Hepatic triglyceride lipase participates with lipoprotein lipase in the hydrolysis of the lipid in very low density lipoproteins, intermediate density lipoproteins, and the larger low density lipoproteins (S(f) 9-12). Thus, hepatic triglyceride lipase appears to function in a parallel role with lipoprotein lipase in the conversion of very low density and intermediate density lipoproteins to low density lipoproteins (S(f) 0-9).

Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways

Cells obtain FAs either from LPL-catalyzed hydrolysis of lipoprotein triglyceride or from unesterified FFAs associated with albumin. LPL also influences uptake of esterified lipids such as cholesteryl and retinyl esters that are not hydrolyzed in the plasma. This process might not involve LPL enzymatic activity. LPL is regulated by feeding/fasting, insulin, and exercise. Although a number of molecules may affect cellular uptake of FFAs, the best characterized is CD36. Genetic deletion of this multiligand receptor reduces FFA uptake into skeletal muscle, heart, and adipose tissue, and impairs intestinal chylomicron production and clearance of lipoproteins from the blood. CD36 is regulated by some of the same factors that regulate LPL, including insulin, muscle contraction, and fasting, in part, via ubiquitination. LPL and CD36 actions in various tissues coordinate biodistribution of fat-derived calories.