Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment.

Accumulation of toxic lipids evokes the unfolded protein response (UPR) and apoptotic death of macrophages and vascular cells in atherosclerotic plaques. Primary macrophages from insulin-resistant ob/ob and insulin receptor (Insr)(-/-) mice display increased apoptosis in response to loading with free cholesterol or oxysterol, but underlying mechanisms have not been elucidated. We show increased activation of all three major branches of the UPR in response to free cholesterol or oxysterol loading in insulin-resistant macrophages.

Homozygosity for an allele encoding deacetylated FoxO1 protects macrophages from cholesterol-induced inflammation without increasing apoptosis.

Objective: Insulin resistance renders macrophages more prone to cholesterol-induced apoptosis by promoting nuclear localization of transcription factor forkhead box transcription factor (Fox) O1. However, FoxO1 also decreases macrophage inflammation, raising the question of how the balance between proapoptotic and antiinflammatory effects is determined. We sought to identify the mechanism whereby FoxO1 dampens inflammation without promoting apoptosis.

Reducing plasma membrane sphingomyelin increases insulin sensitivity.

It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits.

Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet.

Rationale: The complications of atherosclerosis are a major cause of death and disability in type 2 diabetes. Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions.

Objective: To determine whether there is defective efferocytosis in a mouse model of obesity and atherosclerosis.

Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.

Type 2 diabetes is associated with accelerated atherogenesis, which may result from a combination of factors, including dyslipidemia characterized by increased VLDL secretion, and insulin resistance. To assess the hypothesis that both hepatic and peripheral insulin resistance contribute to atherogenesis, we crossed mice deficient for the LDL receptor (Ldlr-/- mice) with mice that express low levels of IR in the liver and lack IR in peripheral tissues (the L1B6 mouse strain). Unexpectedly, compared with Ldlr-/- controls, L1B6Ldlr-/- mice fed a Western diet showed reduced VLDL and LDL levels, reduced atherosclerosis, decreased hepatic AKT signaling, decreased expression of genes associated with lipogenesis, and diminished VLDL apoB and lipid secretion.

Forkhead transcription factors (FoxOs) promote apoptosis of insulin-resistant macrophages during cholesterol-induced endoplasmic reticulum stress.

Objective: Endoplasmic reticulum stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to endoplasmic reticulum stress-associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in type 2 diabetes. However, the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear.

The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis.

Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel 'multi-hit' macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis.

The macrophage at the crossroads of insulin resistance and atherosclerosis.

The macrophage has emerged as an important player in the pathogenesis of both atherosclerosis and insulin resistance. Cross-talk between inflammatory macrophages and adipocytes may be involved in insulin resistance in peripheral tissues. Defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis.

Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions.

Insulin resistance in diabetes and metabolic syndrome is thought to increase susceptibility to atherosclerotic cardiovascular disease, but the underlying mechanisms are poorly understood. To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. Western diet-fed Insr(-/-) recipients developed larger, more complex lesions with increased necrotic cores and increased numbers of apoptotic cells.

Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice.

Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes.

Increased CD36 protein as a response to defective insulin signaling in macrophages.

Accelerated atherosclerosis is a major cause of morbidity and death in insulin-resistant states such as obesity and the metabolic syndrome, but the underlying mechanisms are poorly understood. We show that macrophages from obese (ob/ob) mice have increased binding and uptake of oxidized LDL, in part due to a post-transcriptional increase in CD36 protein. Macrophages from ob/ob mice are also insulin resistant, as shown by reduced expression and signaling of insulin receptors.

Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure.

Liver X receptor/retinoid X receptor (LXR/RXR) transcription factors have been found to induce a number of genes involved in the regulation of cellular cholesterol efflux, including the ATP-binding cassette transporter A1 (ABCA1), which mediates the active efflux of cellular cholesterol and phospholipids to extracellular acceptors, such as apolipoprotein A-I (apoA-I). In a screen for macrophage LXR/RXR target genes, we identified stearoyl-CoA desaturases 1 and 2 (Scd1 and Scd2), and subsequently tested the hypothesis that SCD activity might modulate cellular cholesterol efflux. In HEK 293 cells co-transfection of ABCA1 with either SCD1 or SCD2 inhibited ABCA1-mediated cholesterol efflux but not phospholipid efflux.