Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from ...the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.
In vivo metabolic tests are highly valuable to determine whether atherosclerosis progression in mouse models is accompanied by carbohydrate metabolism alterations such as glucose intolerance and ...insulin resistance. In this chapter, we describe protocols to perform in the mouse glucose and insulin tolerance tests, two metabolic assays which evaluate the glucose tolerance and the insulin sensitivity, respectively.
Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of ...hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.
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•TET2-deficiency-driven clonal hematopoiesis aggravates insulin resistance in aged mice•TET2-deficiency-driven clonal hematopoiesis aggravates insulin resistance in obese mice•TET2-deficiency-driven clonal hematopoiesis increases IL-1β levels in adipose tissue•NLRP3 inhibition prevents the effects of TET2-deficient cells on insulin sensitivity
Somatic-mutation-driven clonal hematopoiesis is emerging as a potent risk factor for a variety of age-related conditions. Fuster et al. show that clonal hematopoiesis driven by TET2 mutations aggravates insulin resistance in mice. These findings support a causal contribution of somatic TET2 mutations to metabolic syndrome and type 2 diabetes.
Aims/hypothesis
Non-alcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus. Progression of NAFLD is mediated, among other things, by activation of inflammatory ...pathways. In the present study, the role of the proinflammatory cytokine LIGHT (TNFSF14) was explored in NAFLD and type 2 diabetes mellitus in mice deficient for the cytokine.
Methods
Light
-deficient (
Light
−/−
) mice and WT controls were fed a regular chow diet (RCD) or a high-fat high-cholesterol diet (HFHCD) for 16 weeks. The expression of LIGHT and its receptors, herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), was investigated in both dietary regimens. Glucose tolerance, insulin sensitivity, non-alcoholic fatty liver (NAFL), systemic and tissue inflammation, and metabolic gene expression were explored in
Light
−/−
and WT mice fed an RCD and an HFHCD. The effect of
Light
deficiency was also evaluated in hepatic tissue and in inflammation in HFHCD-fed
Irs2
+/−
mice with impaired insulin signalling.
Results
Light
deficiency did not have an effect on metabolism, in NAFL or in tissue and systemic inflammation, in RCD-fed WT mice. HVEM and LTβR were markedly increased in livers of HFHCD-fed WT mice compared with RCD-fed WT controls. In WT mice under HFHCD,
Light
deficiency improved glucose tolerance and insulin sensitivity. Non-alcoholic fatty liver disease activity (NAS) score, hepatic CD3
+
T lymphocytes and F4/80
+
macrophages were decreased in HFHCD-fed
Light
−/−
mice compared with HFHCD-fed WT controls. Consistent with a potential role of adipose tissue in hepatic homeostasis,
Light
−/−
mice exhibited augmented anti-inflammatory F4/80
+
CD206
+
adipose tissue macrophages and reduced proinflammatory F4/80
+
CD11c
+
adipose tissue macrophages. Moreover, adipose tissue explants from
Light
−/−
mice showed diminished secretion of monocyte chemoattractant protein 1 (MCP1), TNF-α and IL-17 cytokines. Circulating
Light
−/−
leucocytes consistently displayed augmented levels of the patrolling Ly6C
low
monocytes, decreased Th9 T cell subset and diminished plasma TNF-α and IL-6 levels. Similarly,
Light
deficiency in
Irs2
+/−
mice, which display impaired insulin signalling, also reduced NAFL as well as systemic and adipose tissue inflammation. Analysis of hepatic gene expression in
Light
−/−
mouse livers showed reduced levels of
Zbtb16,
the transcription factor essential for natural killer T (NKT) cell function, and two genes related to NAFLD and fibrosis,
Klf6
and
Tlr4
.
Conclusions/interpretation
These results indicate that
Light
deficiency in HFHCD improves hepatic glucose tolerance, and reduces hepatic inflammation and NAFL. This is accompanied by decreased systemic inflammation and adipose tissue cytokine secretion and by changes in the expression of key genes such as
Klf6
and
Tlr4
involved in NAFLD. These results suggest that therapies to block LIGHT-dependent signalling might be useful to restore hepatic homeostasis and to restrain NAFLD.
•Different mouse models of ageing are available and provide insight into the pathogenic mechanisms of the ageing process.•Genetic background and detailed phenotypic analysis of the available mouse ...models of ageing are important.•There is an urgent need for the development of SOPs and standardized phenotyping in mice, across a range of physiological systems reflecting frailty as seen in patients.•Several pathogenic processes can be modulated by caloric restriction in mouse models of ageing.
Ageing is a process that gradually increases the organism’s vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction.
Background
Obesity is associated with high cardiovascular risk. Postprandial lipidaemia has been associated with cardiovascular disease risk. Our aim was to identify whether anthropometric ...parameters, insulin resistance (IR) and/or fasting plasma triglycerides may determine postprandial changes in lipoprotein concentrations in abdominal and morbid obese subjects.
Methods
We have studied 20 non‐diabetic, normolipidaemic subjects with abdominal obesity, 20 morbid obese subjects and 20 healthy individuals, that have similar age and gender. In all of them a standardised oral fat load test (OFLT) with unsaturated fat was performed.
Results
During the OFLT, the postprandial triglycerides response was significantly higher in subjects with abdominal obesity compared with morbid obese subjects (4 hours triglycerides pick value and AUC of triglycerides). Both obese groups showed significantly higher postprandial triglycerides response compared with healthy subjects. Dividing the obesity group according to the presence of IR, we found that IR was an important factor related with postprandial lipaemia but not BMI or waist circumference. In addition, postprandial glycaemia and insulinaemia significantly decreased in all studied subjects, being the highest decrease in morbid obese subjects and in subjects with IR. Postprandial triglyceridaemia significantly correlated with IR parameters and not with anthropometric parameters in AO and MO subjects.
Conclusion
In subjects with AO and MO, postprandial triglycerides values are higher than healthy individuals and independently predicted by fasting IR parameters. Furthermore, unsaturated fat improved IR state.
Aims/hypothesis
Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In ...the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated.
Methods
Atherosclerosis development was evaluated in
Apoe
−/−
Irs2
+/−
mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in
Apoe
−/−
Irs2
+/−
mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways.
Results
Treatment of
Apoe
−/−
Irs2
+/−
mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6C
high
monocytes and activated T cells. In vitro analysis showed that, in macrophages from
Apoe
−/−
Irs2
+/−
mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques.
Conclusions/interpretation
Lixisenatide decreases atheroma plaque size and instability in
Apoe
−/−
Irs2
+/−
mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.
Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the ...increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.
The development of certain chronic metabolic diseases has been attributed to elevated levels of dietary cholesterol. However, decades of research in animal models and humans have demonstrated a high ...complexity with respect to the impact of dietary cholesterol on the progression of these diseases. Thus, recent investigations in non-alcoholic fatty liver disease (NAFLD) point to dietary cholesterol as a key factor for the activation of inflammatory pathways underlying the transition from NAFLD to non-alcoholic steatohepatitis (NASH) and to hepatic carcinoma. Dietary cholesterol was initially thought to be the key factor for cardiovascular disease development, but its impact on the disease depends partly on the capacity to modulate plasmatic circulating low-density lipoprotein (LDL) cholesterol levels. These studies evidence a complex relationship between these chronic metabolic diseases and dietary cholesterol, which, in certain conditions, might promote metabolic complications. In this review, we summarize rodent studies that evaluate the impact of dietary cholesterol on these two prevalent chronic diseases and their relevance to human pathology.
The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a ...lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.
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