Hyperchylomicronemia causes endothelial cell inflammation and increases atherosclerosis.

The effect of increased triglycerides (TGs) as an independent factor in atherosclerosis development has been contentious, in part, because severe hypertriglyceridemia associates with low levels of low-density lipoprotein cholesterol (LDL-C). To test whether hyperchylomicronemia, in the absence of markedly reduced LDL-C levels, contributes to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (i ) and LDLR knockdown ( ) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL.

FITM2 deficiency results in ER lipid accumulation, ER stress, and reduced apolipoprotein B lipidation and VLDL triglyceride secretion in vitro and in mouse liver.

Objective: Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL.

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.

Background: Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides.

Lipid Disorders and Pregnancy.

Practicing endocrinologists are likely to confront 2 major issues that occur with dyslipidemias during pregnancy. The most dramatic is the development of severe hypertriglyceridemia leading to acute pancreatitis. The second is the approach to treatment of familial hypercholesterolemia, a common genetic disorder.

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis.

Background: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies.

In the Beginning, Lipoproteins Cross the Endothelial Barrier.

Atherosclerosis begins with the infiltration of cholesterol-containing lipoproteins into the arterial wall. White blood cell (WBC)-associated inflammation follows. Despite decades of research using genetic and pharmacologic methods to alter WBC function, in humans, the most effective method to prevent the initiation and progression of disease remains low-density lipoprotein (LDL) reduction.

Intracellular lipase and regulation of the lipid droplet.

Purpose Of Review: Lipid droplets are increasingly recognized as distinct intracellular organelles that have functions exclusive to the storage of energetic lipids. Lipid droplets modulate macrophage inflammatory phenotype, control the availability of energy for muscle function, store excess lipid, sequester toxic lipids, modulate mitochondrial activity, and allow transfer of fatty acids between tissues.

Recent Findings: There have been several major advances in our understanding of the formation, dissolution, and function of this organelle during the past two years.

Burden of cardiometabolic risk factors and vascular health.

Background: Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk.

Continuous glucose monitoring captures glycemic variability in obesity after sleeve gastrectomy: A prospective cohort study.

Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery.

FITM2 deficiency results in ER lipid accumulation, ER stress, reduced apolipoprotein B lipidation, and VLDL triglyceride secretion and in mouse liver.

Objectives: Triglyceride (TG) association with apolipoprotein B100 (apoB100) serves to form very low density lipoproteins (VLDL) in the liver. The repertoire of factors that facilitate this association is incompletely defined. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytoplasmic lipid droplets (LDs) in tissues that do not form VLDL.

Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.

Background: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear.

Methods: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs.

Flipped C-Terminal Ends of APOA1 Promote ABCA1-dependent Cholesterol Efflux by Small HDLs.

Background: Cholesterol efflux capacity (CEC) predicts cardiovascular disease (CVD) independently of HDL cholesterol (HDL-C) levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 pathway, but the underlying mechanisms are unclear.

Methods: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 in the different particles, and the CECs of plasma and isolated HDLs.

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial.

Cardiac lipid metabolism, mitochondrial function, and heart failure.

A fine balance between uptake, storage, and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy-demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions.

Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion.

Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRAS mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME).

Obesity and Overweight: Probing Causes, Consequences, and Novel Therapeutic Approaches Through the American Heart Association's Strategically Focused Research Network.

As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center.

Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3).

The positive relationship between increased levels of circulating triglycerides and cardiovascular events has been observed for decades. Driven by genetic cohort studies, inhibitors of APOC3 (apolipoprotein C3) and ANGPTL (angiopoietin-like protein) 3 that reduce circulating triglycerides are poised to enter clinical practice. We will review the biology of how inhibition of these 2 proteins affects circulating lipoproteins as well as the current state of clinical development of monoclonal antibodies, antisense oligonucleotides, and silencing RNAs targeting APOC3 and ANGPTL3.

Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan.