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issn:0957-96.2
1.  Apolipoprotein A-I Mimetics 
Current opinion in lipidology  2014;25(4):304-308.
Purpose of Review
To summarize recent publications in the field of apolipoprotein mimetics.
Recent Findings
Apolipoprotein mimetic peptides continue to show efficacy in a number of animal models of disease and demonstrate properties that make them attractive as potential therapeutic agents. A number of new apolipoprotein mimetics have been described recently. A major site of action of apolipoprotein mimetic peptides was found to be in the small intestine where they decrease the levels of pro-inflammatory bioactive lipids. A major problem related to the use of apolipoprotein mimetic peptides is their cost, particularly those that need to be generated by solid phase synthesis with chemical addition of end blocking groups. Novel approaches to apolipoprotein mimetic therapy have emerged recently that show promise in overcoming these barriers.
Summary
Despite the recent failure of therapies designed to raise HDL-cholesterol in humans, an approach to therapy using mimetics of HDL and its components continues to show promise.
doi:10.1097/MOL.0000000000000092
PMCID: PMC4213064  PMID: 24977978
Apolipoproteins; Apolipoprotein mimetics; HDL; Atherosclerosis; Cancer
2.  Perilipin 5, a Lipid Droplet Protein Adapted to Mitochondrial Energy Utilization 
Current opinion in lipidology  2014;25(2):110-117.
Purpose of review
We summarize recent mechanistic and physiological studies related to the role of perilipin 5 in regulating lipid droplet accumulation and protection to fatty acids (FAs) in tissues with high lipid oxidative metabolism.
Recent findings
Perilipin 5 (Plin5) is a lipid droplet (LD) targeting protein that promotes association of LDs with mitochondria and is most highly expressed in oxidative tissues, including cardiac and skeletal muscle. Recent in vivo and in vitro data indicate an important role for Plin5 in the regulation of cardiac lipid storage and function. Targeted overexpression of Plin5 in heart causes cardiac steatosis and mild mitochondria dysfunction and hypertrophy, but without affecting cardiac function. In contrast, whole body ablation of Plin5 (Plin5−/− mice) reduces cardiac lipid droplet formation, increases cardiac fatty acid oxidation, and promotes cardiac dysfunction; cardiac defects can be prevented with anti-oxidative therapy. These data suggest a cytoprotective role for Plin5 to promote lipid storage but to limit FA toxicity, parameters critical for tissues with high lipid oxidative metabolism.
Summary
In vivo and in vitro data suggest that Plin5 is part of a cell adaptive response to high lipid oxidative metabolism to protect LD storage against neutral lipases and, so, limit FA accumulation. While the specific mechanisms that underlie Plin5 LD storage protection in oxidative tissues remain to be fully elucidated, Plin5 provides a basis for the novel cytoprotective nature of LDs.
doi:10.1097/MOL.0000000000000057
PMCID: PMC4517968  PMID: 24535284
ATGL; steatosis; β-oxidation; lipolysis; FA toxicity
3.  Regulation of bile acid homeostasis by the intestinal Diet1–FGF15/19 axis 
Current opinion in lipidology  2014;25(2):140-147.
Purpose of review
Hepatic bile acid synthesis is controlled, in part, by a complex enterohepatic feedback regulatory mechanism. In this review, we focus on the role of the intestinal FGF15/19 hormone in modulating bile acid levels, and additional metabolic effects on glucose metabolism, non-alcoholic liver disease (NAFLD), and liver regeneration. We also highlight the newly identified intestinal protein, Diet1, which is a modulator of FGF15/19 levels.
Recent findings
Low FGF19 levels are associated with bile acid diarrhea and NAFLD. In contrast, high FGF19 levels are associated with diabetes remission following Roux-en-Y gastric bypass surgery, suggesting new therapeutic approaches against type 2 diabetes. The effect of FGF15/19 on liver plasticity is a double-edged sword: whereas elevated FGF15/19 levels improve survival of mice after partial hepatectomy, FGF19 mitogenic activity is associated with liver carcinoma. Finally, a recent study has identified Diet1, an intestinal factor that influences FGF15/19 levels in mouse intestine and human enterocytes. Diet1 represents the first factor shown to influence FGF15/19 levels at a post-transcriptional level.
Summary
The biological effects of FGF15/19 make it an attractive target for treating metabolic dysregulation underlying conditions such as fatty liver and type 2 diabetes. Further elucidation of the role of Diet1 in FGF15/19 secretion may provide a control point for pharmacological modulation of FGF15/19 levels.
doi:10.1097/MOL.0000000000000060
PMCID: PMC4497822  PMID: 24535283
enterohepatic circulation; fibroblast growth factor; NAFLD; gastric bypass
4.  Hypobetalipoproteinemia and Abetalipoproteinemia 
Current opinion in lipidology  2014;25(3):161-168.
Purpose of Review
Several mutations in the apoB, PCSK9 and MTP genes result in low or absent levels of apoB and LDL-C in plasma which cause familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Mutations in the ANGPTL3 gene cause familial combined hypolipidemia. Clinical manifestations range from none to severe, debilitating and life-threatening disorders. This review summarizes recent genetic, metabolic and clinical findings and presents an update on management strategies.
Recent findings
Cases of cirrhosis and hepatocellular carcinoma have now been identified in heterozygous FHBL probably due to decreased triglyceride transport capacity from the liver. ANGPTL3 mutations cause low levels of LDL-C and low HDL-C in compound heterozygotes and homozygous subjects, decrease reverse cholesterol transport and lower glucose levels. The effect on atherosclerosis is unknown; however, severe fatty liver has been identified. Loss of function mutations in PCSK-9 cause FHBL which appears to lower risk for CAD and have no adverse sequelae. Phase III clinical trials are now underway examining the effect of PCSK-9 inhibitors on cardiovascular events in combination with statin drugs.
Summary
Mutations causing low LDL-C and apoB have provided insight into lipid metabolism, disease associations and the basis for drug development to lower LDL-C in disorders causing high levels of cholesterol. Early diagnosis and treatment is necessary to prevent adverse sequelae from FHBL and ABL.
doi:10.1097/MOL.0000000000000072
PMCID: PMC4465983  PMID: 24751931
Hypobetalipoproteinemia; abetalipoproteinemia; combined hypolipidemia; angiopoietin-like 3 protein; PCSK9
5.  Intestinal Lipid Absorption and Lipoprotein Formation 
Current opinion in lipidology  2014;25(3):200-206.
Purpose of review
The purpose of this review is to summarize evidence for the presence of two pathways of lipid absorption and their regulation.
Recent findings
Lipid absorption involves hydrolysis of dietary fat in the lumen of the intestine followed by the uptake of hydrolyzed products by enterocytes. Lipids are re-synthesized in the endoplasmic reticulum and are either secreted with chylomicrons and high density lipoproteins or stored as cytoplasmic lipid droplets. Lipids in the droplets are hydrolyzed and are secreted at a later time. Secretion of lipids by the chylomicron and HDL pathways are critically dependent on MTP and ABCA1, respectively, and are regulated independently. Gene ablation studies showed that MTP function and chylomicron assembly is essential for the absorption of triglyceride and retinyl esters. Ablation of MTP abolishes triglyceride absorption and results in massive triglyceride accumulation in enterocytes. Although majority of phospholipid, cholesterol and vitamin E are absorbed through the chylomicron pathway, a significant amount of these lipids are also absorbed via the HDL pathway. Chylomicron assembly and secretion is increased by the enhanced availability of fatty acids, whereas HDL pathway is upregulated by LXR agonists. Intestinal insulin resistance increases chylomicron and might reduce HDL production.
Summary
Triglycerides are exclusively transported via the chylomicron pathway and this process is critically dependent on MTP. Besides chylomicrons, absorption of phospholipids, free cholesterol, retinol, and vitamin E also involves high density lipoproteins. These two pathways are complementary and are regulated independently. They may be targeted to lower lipid absorption in order to control hyperlipidemia, obesity, metabolic syndrome, steatosis, insulin resistance, atherosclerosis and other disorders.
doi:10.1097/MOL.0000000000000084
PMCID: PMC4265799  PMID: 24751933
Chylomicron; triglyceride; cholesterol; vitamin E; MTP; ABCA1; ACAT2; intestine; lipid absorption
6.  Clinical significance of apolipoprotein A5 
Current opinion in lipidology  2008;19(4):349-354.
Purpose of review
We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene–environment interactions in relation to cardiovascular disease and its common risk factors.
Recent findings
Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks.
Summary
Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk.
doi:10.1097/MOL.0b013e328304b681
PMCID: PMC4428951  PMID: 18607181
apolipoprotein A-V; cardiovascular disease; diet; gene–environment interaction; pharmacogenomics; plasma lipids
7.  Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism 
Current opinion in lipidology  2015;26(2):88-95.
Purpose of review
Glucokinase regulator (GCKR) encodes glucokinase regulatory protein (GKRP), a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase (GCK). Genome-wide association studies have identified a common coding variant within GCKR associated with multiple metabolic traits. This review focuses on recent insights into the critical role of GKRP in hepatic glucose metabolism that have stemmed from the study of human genetics. This knowledge has improved our understanding of glucose and lipid physiology and informed the development of targeted molecular therapeutics for diabetes.
Recent findings
Rare GCKR variants have effects on GKRP expression, localization, and activity. These variants are collectively associated with hypertriglyceridaemia but are not causal. Crystal structures of GKRP and the GCK–GKRP complex have been solved, providing greater insight into the molecular interactions between these proteins. Finally, small molecules have been identified that directly bind GKRP and reduce blood glucose levels in rodent models of diabetes.
Summary
GCKR variants across the allelic spectrum have effects on glucose and lipid homeostasis. Functional analysis has highlighted numerous molecular mechanisms for GKRP dysfunction. Hepatocyte-specific GCK activation via small molecule GKRP inhibition may be a new avenue for type 2 diabetes treatment, particularly considering evidence indicating GKRP loss-of-function alone does not cause hypertriglyceridaemia.
doi:10.1097/MOL.0000000000000155
PMCID: PMC4422901  PMID: 25692341
diabetes therapy; glucokinase regulator; glucokinase regulatory protein; glucose homeostasis; hypertriglyceridaemia
8.  Atherosclerosis: cell biology and lipoproteins 
Current opinion in lipidology  2013;24(5):455-456.
doi:10.1097/MOL.0b013e3283654ef9
PMCID: PMC4382098  PMID: 24005221
9.  [No title available] 
PMCID: PMC3947892  PMID: 24366230
10.  [No title available] 
PMCID: PMC4018574  PMID: 24362355
11.  Adverse metabolic effects of dietary fructose: Results from recent epidemiological, clinical, and mechanistic studies 
Current opinion in lipidology  2013;24(3):198-206.
Purpose of review
The effects of dietary sugar on risk factors and processes associated with metabolic disease remains a controversial topic, with recent reviews of the available evidence arriving at widely discrepant conclusions.
Recent findings
There are many recently published epidemiological studies that provide evidence that sugar consumption is associated with metabolic disease. Three recent clinical studies, which investigated the effects of consuming relevant doses of sucrose or high fructose corn syrup along with ad libitum diets, provide evidence that consumption of these sugars increase risk factors for cardiovascular disease (CVD) and metabolic syndrome. Mechanistic studies suggest that these effects result from the rapid hepatic metabolism of fructose catalyzed by fructokinase C, which generates substrate for de novo lipogenesis and leads to increased uric acid levels. Recent clinical studies investigating the effects of consuming less sugar, via educational interventions or by substitution of sugar-sweetened beverages for non-calorically sweetened beverages, provide evidence that such strategies have beneficial effects on risk factors for metabolic disease or on BMI in children.
Summary
The accumulating epidemiological evidence, direct clinical evidence, and the evidence suggesting plausible mechanisms support a role for sugar in the epidemics of metabolic syndrome, CVD and type 2 diabetes.
doi:10.1097/MOL.0b013e3283613bca
PMCID: PMC4251462  PMID: 23594708
Fructose; sucrose; high fructose corn syrup; sugar; metabolic disease
12.  Estrogens and Cardiovascular Disease Risk Revisited: the Women’s Health Initiative 
Current opinion in lipidology  2013;24(6):493-499.
Purpose of Review
In 2002 and 2004, the Women’s Health Initiative (WHI) found no evidence that hormone therapy (HT) with estrogen or estrogen with progestin (E+P) protected against cardiovascular disease (CVD). Since then, further analyses have been performed. This review summarizes current analyses on the effects of HT on CVD and CVD risk factors.
Recent Findings
The negative effects of HT vary by type of CVD event. Estrogen alone and E+P show consistent effects on CVD, but E+P has more impact on coronary heart disease (CHD) and venous thromboembolism (VTE). Women of all ethnicities, including those who are obese, have diabetes, or are taking daily aspirin or statins remain at risk for adverse effects from HT. While younger women or more recently menopausal women taking HT may be at relatively lower risk for CHD and myocardial infarction, they remain at risk for stroke, VTE, and peripheral artery disease. Adverse effects are enhanced in older women with menopausal symptoms. While HT lowers low-density lipoprotein cholesterol (LDL-C) and Lipoprotein (a) and raises high-density lipoprotein cholesterol, it has adverse effects on triglyceride, lipoprotein composition, and inflammatory and hemostatic markers. Baseline metabolic syndrome and high LDL-C increase the CHD risk with HT. Analyses of discontinuation data in the estrogen-alone and E+P trials suggest that the adverse effects of HT on CVD are reversible.
Summary
Recent analyses do not justify postmenopausal HT for CVD prevention. Further research on the role of HT-induced changes in CVD risk factors along with genetic studies may increase understanding and aid in developing safer therapies for menopausal symptoms.
doi:10.1097/MOL.0000000000000022
PMCID: PMC4219554  PMID: 24184944
Cardiovascular disease; hormone therapy; CVD risk factors; Women’s Health Initiative
13.  Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism 
Current opinion in lipidology  2008;19(3):248-256.
Purpose of review
Stearoyl-coenzyme A desaturase 1 is a δ-9 fatty acid desaturase that catalyzes the synthesis of monounsaturated fatty acids and has emerged as a key regulator of metabolism. This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease.
Recent findings
scd1-deficient mice have reduced lipid synthesis and enhanced lipid oxidation, thermogenesis and insulin sensitivity in various tissues including liver, muscle and adipose tissue due to transcriptional and posttranscriptional effects. These metabolic changes protect scd1-deficient mice from a variety of dietary, pharmacological and genetic conditions that promote obesity, insulin resistance and hepatic steatosis. Stearoylcoenzyme A desaturase 1 is required to guard against dietary unsaturated fat deficiency, leptin deficiency-induced diabetes, and palmitate-induced lipotoxic insults in muscle and pancreatic β-cells. Paradoxical observations of increased muscle stearoyl-coenzyme A desaturase 1 during obesity, starvation and exercise raise questions as to the role of stearoyl-coenzyme A desaturase 1 in this tissue. Mice with a liver-specific loss of stearoyl-coenzyme A desaturase 1, and inhibition of stearoyl-coenzyme A desaturase 1 via antisense or RNA interference, recapitulate only a subset of the phenotypes observed in global Scd1 deficiency, indicating the involvement of multiple tissues.
Summary
Recent studies in humans and animal models have highlighted that modulation of stearoyl-coenzyme A desaturase 1 activity by dietary intervention or genetic manipulation strongly influences several facets of energy metabolism to affect susceptibility to obesity, insulin resistance, diabetes and hyperlipidemia.
doi:10.1097/MOL.0b013e3282f9b54d
PMCID: PMC4201499  PMID: 18460915
diabetes; insulin resistance; obesity; oleate; stearoyl-CoA desaturase
14.  Thrombospondins: Old Players, New Games 
Current opinion in lipidology  2013;24(5):401-409.
Purpose of review
Thrombospondins (TSPs) are secreted extracellular matrix (ECM) proteins from TSP family, which consists of five homologous members. They share a complex domain structure and have numerous binding partners in ECM and multiple cell surface receptors. Information that has emerged over the last decade identifies TSPs as important mediators of cellular homeostasis, assigning new important roles in cardiovascular pathology to these proteins.
Recent findings
Recent studies of the functions of TSP in the cardiovascular system, diabetes and aging, which placed several TSPs in a position of critical regulators, demonstrated the involvement of these proteins in practically every aspect of cardiovascular pathophysiology related to atherosclerosis: inflammation, immunity, leukocyte recruitment and function, function of vascular cells, angiogenesis, and responses to hypoxia, ischemia and hyperglycemia. TSPs are also critically important in the development and ultimate outcome of the complications associated with atherosclerosis – myocardial infarction and heart hypertrophy and failure. Their expression and significance increase with age and with the progression of diabetes, two major contributors to the development of atherosclerosis and its complications.
Summary
This overview of recent literature examines the latest information on the newfound functions of TSPs that emphasize the importance of ECM in cardiovascular homeostasis and pathology. The functions of TSPs in myocardium, vasculature, vascular complications of diabetes, aging and immunity are discussed.
doi:10.1097/MOL.0b013e3283642912
PMCID: PMC3935726  PMID: 23892609
thrombospondin; extracellular matrix; cardiovascular system
15.  Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native LDL particles 
Current opinion in lipidology  2011;22(5):386-393.
Purpose of review
Because early findings indicated that native low density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in vitro incubations, investigators presumed that LDL must be modified in some way to trigger its uptake by the macrophage. The purpose of this review is to discuss recent findings showing that native unmodified LDL can induce massive macrophage cholesterol accumulation mimicking macrophage foam cell formation that occurs within atherosclerotic plaques.
Recent findings
Macrophages that show high rates of fluid-phase pinocytosis also show similar high rates of uptake of native unmodified LDL through non-receptor mediated uptake within both macropinosomes and micropinosomes. Non-saturable fluid-phase uptake of LDL by macrophages converts the macrophages into foam cells. Different macrophage phenotypes demonstrate either constitutive fluid-phase pinocytosis or inducible fluid-phase pinocytosis. Fluid-phase pinocytosis has been demonstrated by macrophages within mouse atherosclerotic plaques indicating that this pathway contributes to plaque macrophage cholesterol accumulation.
Summary
Contrary to what has been believed previously, macrophages can take up large amounts of native unmodified LDL by receptor-independent, fluid-phase pinocytosis converting these macrophages into foam cells. Thus, targeting macrophage fluid-phase pinocytosis should be considered when investigating strategies to limit macrophage cholesterol accumulation in atherosclerotic plaques.
doi:10.1097/MOL.0b013e32834adadb
PMCID: PMC4174540  PMID: 21881499
LDL; macrophages; fluid-phase pinocytosis; cholesterol; macropinocytosis
16.  Comparative gene identification-58/α/β hydrolase domain 5: more than just an adipose triglyceride lipase activator? 
Current opinion in lipidology  2014;25(2):102-109.
Purpose of review
Comparative gene identification-58 (CGI-58) is a lipid droplet-associated protein that controls intracellular triglyceride levels by its ability to activate adipose triglyceride lipase (ATGL). Additionally, CGI-58 was described to exhibit lysophosphatidic acid acyl transferase (LPAAT) activity. This review focuses on the significance of CGI-58 in energy metabolism in adipose and nonadipose tissue.
Recent findings
Recent studies with transgenic and CGI-58-deficient mouse strains underscored the importance of CGI-58 as a regulator of intracellular energy homeostasis by modulating ATGL-driven triglyceride hydrolysis. In accordance with this function, mice and humans that lack CGI-58 accumulate triglyceride in multiple tissues. Additionally, CGI-58-deficient mice develop an ATGL-independent severe skin barrier defect and die soon after birth. Although the premature death prevented a phenotypical characterization of adult global CGI-58 knockout mice, the characterization of mice with tissue-specific CGI-58 deficiency revealed new insights into its role in neutral lipid and energy metabolism. Concerning the ATGL-independent function of CGI-58, a recently identified LPAAT activity for CGI-58 was shown to be involved in the generation of signaling molecules regulating inflammatory processes and insulin action.
Summary
Although the function of CGI-58 in the catabolism of cellular triglyceride depots via ATGL is well established, further studies are required to consolidate the function of CGI-58 as LPAAT and to clarify the involvement of CGI-58 in the metabolism of skin lipids.
doi:10.1097/MOL.0000000000000058
PMCID: PMC4170181  PMID: 24565921
cardiomyopathy; hepatosteatosis; ichthyosis; lipid signaling; lipolysis
17.  Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance 
Current opinion in lipidology  2008;19(1):16-24.
Purpose of review
Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome.
Recent findings
The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance.
Summary
Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome.
doi:10.1097/MOL.0b013e3282f2b24a
PMCID: PMC4151171  PMID: 18196982
dyslipidemia; free fatty acids; fructose consumption; hepatic steatosis; insulin resistance; metabolic syndrome
18.  Parkin in the regulation of fat uptake and mitochondrial biology emerging links in the pathophysiology of Parkinson’s Disease 
Current opinion in lipidology  2012;23(3):201-205.
Purpose of review
Perturbations in fatty acid levels and in regulatory proteins linked to fat and mitochondrial homeostasis are associated with modifying the risk of Parkinson Disease (PD). Findings, that are not surprising, based on the high fat content of the brain, the myriad of neurological functions dependent on polyunsaturated fatty acids and the role of mitochondria in energy supply and stress amelioration. Nevertheless, dissecting out the molecular links between lipid biology, mitochondrial regulation and PD is complicated by the divergent etiologies underpinning PD pathophysiology. Here, we summarize aspects of fatty acid biology relevant to PD; the known links between the modulation of fat and PD; and introduce mechanisms whereby the E3-ubiquitin ligase, Parkin know to be mutated as a genetic predisposing factor in PD, modulates fat uptake and mitochondrial control.
Recent Findings
Prior evidence supports that Parkin, under mitochondrial stress conditions, plays a pivotal role in the mitophagy mitochondrial housekeeping program. Recent evidence now demonstrates a broader role of Parkin in controlling fat uptake and mitochondrial regulatory programs.
Summary
The identification that Parkin has a multifunctional role in modulating cellular fatty acid uptake and mitochondrial biology further strengthens the pathophysiologic link between fat metabolism, mitochondria, and Parkinson Disease.
doi:10.1097/MOL.0b013e328352dc5d
PMCID: PMC4151552  PMID: 22488424
Parkin; CD36; fat uptake; PGC-1α
19.  Omega-3 fatty acids: mechanisms underlying “protective effects” in atherosclerosis 
Current opinion in lipidology  2013;24(4):345-350.
Purpose of review
This article provides an updated review on mechanistic and molecular studies relating to the effects of n-3 fatty acids (FA) on inhibiting atherogenesis.
Recent findings
The effects of n-3 FA on modulating arterial lipoprotein lipase (LpL) levels link to changes in lipid deposition in the arterial wall. LpL expression in the arterial wall also relates to local macrophage-mediated inflammatory processes. Increasing evidence suggests that n-3 FA ameliorate inflammation, another key component in the development of atherosclerosis, including decreases in pro-inflammatory cytokine production. n-3 FA inhibit atherogenic signaling pathways and modulate the phenotypes of inflammatory leukocytes and their recruitment in the arterial wall.
Summary
New mechanistic insights into the anti-atherogenic action of n-3 FA have emerged. These studies may contribute to future therapeutic advances in preventing mortality and morbidity associated with atherosclerosis.
doi:10.1097/MOL.0b013e3283616364
PMCID: PMC3918949  PMID: 23594712
Atherosclerosis; inflammation; lipoprotein lipase; macrophages; n-3 fatty acids
20.  New developments in selective cholesteryl ester uptake 
Current opinion in lipidology  2013;24(5):386-392.
Purpose of review
Selective lipid uptake (SLU) is known to be a major pathway of lipoprotein cholesterol metabolism in experimental animals and humans, but remains poorly understood. This review provides a brief overview of SLU mediated by the HDL receptor scavenger receptor B-type I (SR-BI), and highlights several surprising new findings related to the impact of SLU pathways in cholesterol homeostasis.
Recent findings
Under certain conditions, SR-BI-mediated SLU contributes to reverse cholesterol transport (RCT) independently of ABCG5/G8-mediated biliary cholesterol secretion, implying a novel trafficking mechanism. Hepatic SR-BI expression and RCT are decreased in diabetic mice. Farnesoid X receptor (FXR) and the microRNAs miR-185, miR-96 and miR-223 are emerging therapeutic targets for increasing SR-BI expression. SR-BI-independent selective cholesteryl ester uptake is a newly characterized pathway in macrophage foam cells.
Summary
New findings underscore the importance of SR-BI-mediated SLU in hepatic SLU and RCT, while indicating that further investigation is needed to define SLU pathways, including SR-BI-independent macrophage selective cholesteryl ester uptake. The intracellular trafficking of cholesterol in these pathways appears to be critical to their normal function and is a major subject of ongoing studies.
doi:10.1097/MOL.0b013e3283638042
PMCID: PMC4096242  PMID: 23842142
HDL cholesterol; macrophage foam cell; reverse cholesterol transport; scavenger receptor B-type I; selective cholesteryl ester uptake
21.  Oxidation-specific epitopes as targets for biotheranostic applications in humans: Biomarkers, molecular imaging and therapeutics 
Current opinion in lipidology  2013;24(5):426-437.
Purpose of Review
Emerging data demonstrates the potential of translational applications of antibodies directed against oxidation-specific epitopes (OSE). “Biotheranostics” in cardiovascular disease (CVD) describes targeting of OSE for biomarker, therapeutic and molecular imaging diagnostic applications.
Recent findings
Lipid oxidation collectively yields a large variety of oxidation-specific epitopes (OSE), such as oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes. OSE are immunogenic, pro-inflammatory, pro-atherogenic and plaque destabilizing and represent danger associated molecular patterns (DAMPs). DAMPs are recognized by the innate immune system via pattern recognition receptors, including scavenger receptors IgM natural antibodies and complement factor H (CFH), that bind, neutralize and/or facilitate their clearance. Biomarker assays measuring OxPL present on apolipoprotein B-100 lipoproteins, and particularly on lipoprotein (a), predict the development of CVD events. In contrast, OxPL on plasminogen facilitate fibrinolysis and may reduce atherothrombosis. Oxidation-specific antibodies (OSA) attached to magnetic nanoparticles image lipid-rich, oxidation-rich plaques. Infusion or overexpression of OSA reduces the progression of atherosclerosis, suggesting that they may be used in similar applications in humans.
Summary
Using the accelerating knowledge base and improved understanding of the interplay of oxidation, inflammation and innate and adaptive immunity in atherogenesis, emerging clinical applications of OSA may identify, monitor and treat CVD in humans.
doi:10.1097/MOL.0b013e328364e85a
PMCID: PMC4085330  PMID: 23995232
biotheranostic; oxidation; innate immunity; atherogenesis; molecular imaging
22.  Phospholipase A2 enzymes in metabolic and cardiovascular diseases 
Current opinion in lipidology  2012;23(3):235-240.
Purpose of review
The phospholipase A2 (PLA2) family of proteins includes lipolytic enzymes that liberate the sn-2 fatty acyl chains from phospholipids to yield non-esterified fatty acids and lysophospholipids. The purpose of this review is to discuss recent findings showing distinct roles of several of these PLA2 enzymes in inflammatory metabolic diseases such as diabetes and atherosclerosis.
Recent findings
The Group 1B PLA2 (PLA2G1B) digestion of phospholipids in the intestinal lumen facilitates postprandial lysophospholipid absorption, which suppresses hepatic fatty acid oxidation leading to increased VLDL synthesis, decreased glucose tolerance, and promotion of tissue lipid deposition to accentuate diet-induced obesity, diabetes, and hyperlipidemia. Other secretory PLA2s promote inflammatory metabolic diseases by generating bioactive lipid metabolites to induce inflammatory cytokine production, whereas the major intracellular PLA2s, cPLA2α and iPLA2, generate arachidonic acid and lysophosphatic acid in response to extracellular stimuli to stimulate leukocyte chemotactic response.
Summary
Each member of the phospholipase A2 family of enzymes serves a distinct role in generating active lipid metabolites that promote inflammatory metabolic diseases including atherosclerosis, hyperlipidemia, obesity, and diabetes. The development of specific drugs that target one or more of these PLA2 enzymes may be novel strategies for treatment of these chronic inflammatory metabolic disorders.
doi:10.1097/MOL.0b013e328351b439
PMCID: PMC4062387  PMID: 22327613
Obesity; diabetes; hyperlipidemia; atherosclerosis; inflammation; lysophospholipid
23.  Acyl-coenzyme A synthetases in metabolic control 
Current opinion in lipidology  2010;21(3):212-217.
Purpose of review
The 11 long-chain (ACSL) and very long chain acyl-coenzyme A (acyl-CoA) synthetases [(ACSVL)/fatty acid transport protein] are receiving considerable attention because it has become apparent that their individual functions are not redundant.
Recent findings
Recent studies have focused on the structure of the acyl-CoA synthetases, their post-translational modification, their ability to activate fatty acids of varying chain lengths, and their role in directing fatty acids into different metabolic pathways. An unsettled controversy focuses on the ACSVL isoforms and whether these have both enzymatic and transport functions. Another issue is whether conversion of a fatty acid to an acyl-CoA produces an increase in the AMP/ATP ratio that is sufficient to activate AMP-activated kinase.
Summary
FuturestudiesarerequiredtodeterminethesubcellularlocationofeachACSLandACSVL isoform and the functional importance of phosphorylation and acetylation. Purification and crystallization of mammalian ACSL and ACSVL isoforms is needed to confirm the mechanism of action and discover how these enzymesdiffer in their affinity for fatty acids of differentchainlengths.Functionally,itwillbeimportanttolearnhowtheACSLisoformscan direct their acyl-CoA products toward independent downstream pathways.
PMCID: PMC4040134  PMID: 20480548
β-oxidation; acyl-CoA synthetase; AMP-activated kinase; fatty acid; fatty acid transport protein; glycerolipid synthesis
24.  Phenotypic modulation of macrophages in response to plaque lipids 
Current opinion in lipidology  2011;22(5):335-342.
Purpose of review
The accumulation of macrophages in the vascular wall is a hallmark of atherosclerosis. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition and stability. In atherosclerotic plaques, macrophages encounter a microenvironment that is comprised of a variety of lipid oxidation products, each of which has diverse biological effects. In this review, we summarize recent advances in our understanding of the effects of plaque lipids on macrophage phenotypic polarization.
Recent findings
Atherosclerotic lesions in mice and in humans contain various macrophage phenotypes, which play different roles in mediating inflammation, the clearance of dead cells, and possibly resolution. Macrophages alter their phenotype and biological function in response to plaque lipids through the upregulation of specific sets of genes. Interaction of oxidized lipids with pattern recognition receptors and activation of the inflammasome by cholesterol crystals drive macrophages towards an inflammatory M1 phenotype. A new phenotype, Mox, develops when oxidized phospholipids activate stress response genes via Nrf2. Other lipid mediators such as nitrosylated-fatty acids and omega-3 fatty acid-derived products polarize plaque macrophages towards anti-inflammatory and proresolving phenotypes.
Summary
A deeper understanding of how lipids that accumulate in atherosclerotic plaques affect macrophage phenotype and function and thus atherosclerotic lesion development and stability will help to devise novel strategies for intervention.
doi:10.1097/MOL.0b013e32834a97e4
PMCID: PMC3979355  PMID: 21841486
Macrophages; oxidized lipids; atherosclerosis; inflammation
25.  Alternative splicing in regulation of cholesterol homeostasis 
Current opinion in lipidology  2013;24(2):147-152.
Purpose of review
With the advent of whole-transcriptome sequencing, or RNA-seq, we now know that alternative splicing is a generalized phenomenon, with nearly all multi-exonic genes subject to alternative splicing. In this review we highlight recent studies examining alternative splicing as a modulator of cellular cholesterol homeostasis, and as an underlying mechanism of dyslipidemia.
Recent findings
A number of key genes involved in cholesterol metabolism are known to undergo functionally relevant alternative splicing. Recently, we have identified coordinated changes in alternative splicing in multiple genes in response to alteration in cellular sterol content. We and others have implicated several splicing factors as regulators of lipid metabolism. Furthermore, a number of cis-acting human gene variants that modulate alternative splicing have been implicated in a variety of human metabolic diseases.
Summary
Alternative splicing is of importance in various types of genetically influenced dyslipidemias, and in the regulation of cellular cholesterol metabolism.
doi:10.1097/MOL.0b013e32835cf284
PMCID: PMC3667406  PMID: 23314925
PTBP1; HMGCR; LDLR; statin; SFRS10

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