Faculty Bibliography

OBJECTIVE:. In adipose, less macrophage lipid accumulation was found with global but not myeloid-specific LpL deficiency. Neither deletion affected the expression of inflammatory genes. Global LpL deficiency also reduced the numbers of elicited peritoneal macrophages. Finally, we assessed gene expression in macrophages from atherosclerotic lesions during regression; LpL deficiency did not affect the polarity of plaque macrophages. CONCLUSIONS:The phenotypic changes observed in macrophages upon deletion of Lpl in vitro is not mimicked in tissue macrophages.

Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild type and diabetic (leptin receptor deficient - db/db) mice. Mice treated with tesaglitazar-containing chow or high fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1-/- mice. Our data shows that drugs, which activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance likely due to competition between these two transcription factors.

Lipins play important roles in adipogenesis, insulin sensitivity, and gene regulation, and mutations in these genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. While all lipins (lipin 1, 2, and 3) act as phosphatidic acid phosphatase (PAP) enzymes, which are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate, lipin 1 has been the focus of most of the lipin-related research. In the current issue of the JCI, Zhang et al. show that while lipin 2 and 3 are expendable for the incorporation of dietary fatty acids into triglycerides, lipin 2/3 PAP activity has a critical role in phospholipid homeostasis and chylomicron assembly in enterocytes.

We assessed the importance of triglyceride (TG) lipolysis and circulating HDL levels in the resolution of atherosclerosis and the phenotype of vascular macrophages. We hypothesized that hyperTG impairs atherosclerosis regression due to decreased HDL particle numbers (HDL-P) and/or HDL function assessed as Cholesterol Efflux Capacity (CEC). To study hyperTG, we performed atherosclerosis regression studies in control Lipoprotein lipase (LpL) flox (LpLfl/fl) and tamoxifen inducible LpL KO (iLpL-/-) mice; the latter showing plasma TG of ~500mg/dL after tamoxifen treatment. We used two different atherosclerosis regression models – the aortic transplant and inhibition of the LDL receptor (LDLR) using antisense oligonucleotides followed by re-expression after ASO discontinuation. We analyzed atherosclerosis regression (lesion size and CD68+ macrophages) in aortic arches, roots and branchiocephalic …

Although LDL is thought to be predominantly produced by lipoprotein lipase (LpL) mediated hydrolysis of VLDL, we show that another pathway for LDL production exists and is evident with deletion of the LDL receptor (LDLR). Plasma LDL levels in humans and animals with LpL loss have been interpreted as demonstrating the obligate requirement for lipolysis in LDL production. However, studies in isolated hepatocytes and kinetic analyses in humans have indicated that in addition to decreased catabolism, reductions in the LDL receptor lead to increased direct LDL production. We first quantified lipids in plasma fractions in mice with inducible deletion of LpL (iLpl-/-) on chow diet. As expected, loss of LpL led to reduced plasma LDL cholesterol levels of 3±0.5 mg/dl compared to 20±6 mg/dl in control Lpl floxed mice (Lplfl/fl), consistent with the importance of the VLDL to LDL pathway in LDL production. HDL was also …

BACKGROUND:The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol-induced hepatic triglyceride accumulation. As the sole enzymes catalyzing the final step in triglyceride synthesis, Diacylglycerol O-acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol-induced hepatic triglyceride accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis. METHODS:mice. RESULTS:mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high-fat diet, but not a low-fat diet. CONCLUSIONS:dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high-fat diet, DGAT1 predominates.

OBJECTIVE:Systemic inflammation contributes to cardiovascular disease in patients with type 2 diabetes, and elevated white blood cell (WBC) counts are an established risk factor. Our goal is to describe changes in WBCs and inflammatory markers after glycemic reductions in diabetes. RESEARCH DESIGN AND METHODS/METHODS:This study enrolled 63 subjects with poorly controlled diabetes, defined as hemoglobin A1c (HbA1c) ≥8% [64 mmol/mol]. Circulating granulocytes and mononuclear cells were separated by histopaque double-density protocol. Inflammatory markers from these isolated WBCs were assessed at baseline and after 3 months of medical management. RESULTS:After 3 months, significant glycemic reduction, defined as a decrease in HbA1c ≥ 1.5%, occurred in 42 subjects. Fasting plasma glucose decreased by 47% (165.6 mg/dL), and HbA1c decreased from 10.2 ± 1.8 to 6.8 ± 0.9. Glycemic reductions were associated with a 9.4% decrease in total WBC counts, 10.96% decrease in neutrophils, and 21.74% decrease in monocytes. The mRNA levels of inflammatory markers from granulocytes and mononuclear cells decreased, including receptor for advanced glycation endproducts; S100 calcium binding proteins A8, A9, A12; krüppel-like factor 5; and IL-1. Also, circulating levels of IL-1β and C-reactive protein decreased. Insulin dose was a mediator between HbA1c and both total WBC and neutrophil counts, but not changes in WBC inflammatory markers. In contrast, the 17 subjects without significant glycemic reductions showed no significant differences in their WBC counts and proteins of inflammatory genes. CONCLUSION/CONCLUSIONS:Significant glycemic reduction in subjects with poorly controlled diabetes led to reduced circulating WBC counts and inflammatory gene expression.

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.