Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies ranging from uncomplicated hepatic fat accumulation to a state of lobular inflammation and hepatocyte ballooning, known ...as non-alcoholic steatohepatitis (NASH). Currently, there are no reliable biomarkers or effective therapeutic options established for NAFLD. Nevertheless, there are several molecular targets in the pipeline, of which fibroblast growth factor 21 (FGF21) is one. FGF21 is secreted primarily from liver and has a plethora of metabolic functions. Pre-clinical and epidemiological studies indicate a relationship between circulating FGF21 levels and hepatic fat content in both mice and humans. Moreover, animal studies have clearly shown that aberrant FGF21 signalling is a key pathological step in the development and progression of NAFLD. A recent Phase II clinical trial demonstrated that administration of an FGF21 analogue significantly reduced hepatic fat in subjects with NASH. As such, FGF21 provides a novel target for future biomarker and therapeutic studies. This review appraises preclinical data to outline the current understanding of FGF21 function in both normal hepatic function and NAFLD. Epidemiological evidence is explored to delineate the relationship between circulating FGF21 levels and NAFLD in humans. Finally, we review the therapeutic effects of FGF21 in the treatment of NAFLD.
•FGF21 is a key regulator of hepatic glucose and lipid metabolism.•FGF21 resistance increases fatty acid supply to the liver and reduces fatty acid utilisation.•Hepatic fatty acid accumulation promotes lipotoxicity.•Circulating FGF21 levels are elevated in patients with NAFLD.•FGF21 mimetics are effective at reducing hepatic steatosis and inflammation.
Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C ...is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.
Background Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with periprocedural myocardial infarction, as ...a result of microvascular obstruction via pro-inflammatory and prothrombotic pathways. Colchicine is a well-established anti-inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS have not been explored. Methods and Results Sixty patients (40 ACS; 20 stable angina pectoris) were prospectively recruited and allocated to colchicine or no treatment. Within 24 hours of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 patients with ACS post-PCI and 4 healthy controls were treated in vitro with colchicine (25 nmol/L) and stimulated with either ionomycin (5 μmol/L) or phorbol 12-myristate 13-acetate (50 nmol/L). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst 3342 and anti-alpha tubulin. Baseline characteristics were similar across both treatment and control arms. Patients with ACS had higher NET release versus patients with stable angina pectoris (
<0.001), which was reduced with colchicine treatment (area under the curve: 0.58 versus 4.29;
<0.001). In vitro, colchicine suppressed unstimulated (
<0.001), phorbol 12-myristate 13-acetate-induced (
=0.009) and ionomycin-induced (
=0.002) NET formation in neutrophils isolated from patients with ACS post-PCI, but not healthy controls. Tubulin organization was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions Colchicine suppresses NET formation in patients with ACS post-PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomized trials powered for clinical end points. Registration URL: https://anzctr.org.au; Unique identifier: ACTRN12619001231134.
Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of ...cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized.
There is compelling evidence from human population studies that plasma levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk. Identification of this ...relationship has stimulated research designed to understand how HDL metabolism is regulated. The ultimate goal of these studies has been to develop HDL-raising therapies that have the potential to decrease the morbidity and mortality associated with atherosclerotic cardiovascular disease. However, the situation has turned out to be much more complex than originally envisaged. This is partly because the HDL fraction consists of multiple subpopulations of particles that vary in terms of shape, size, composition, and surface charge, as well as in their potential cardioprotective properties. This heterogeneity is a consequence of the continual remodeling and interconversion of HDL subpopulations by multiple plasma factors. Evidence that the remodeling of HDLs may impact on their cardioprotective properties is beginning to emerge. This serves to highlight the importance of understanding not only how the remodeling and interconversion of HDL subpopulations is regulated but also how these processes are affected by agents that increase HDL levels. This review provides an overview of what is currently understood about HDL metabolism and how the subpopulation distribution of these lipoproteins is regulated.
Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein ...fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib.
Purpose of the Review
Apolipoprotein (APO) A1, the main apolipoprotein of plasma high-density lipoproteins (HDLs), has several well documented cardioprotective functions. A number of additional ...potentially beneficial functions of APOA1 have recently been identified. This review is concerned with the therapeutic potential of all of these functions in multiple disease states.
Recent Findings
Knowledge of the beneficial functions of APOA1 in atherosclerosis, thrombosis, diabetes, cancer, and neurological disorders is increasing exponentially. These insights have led to the development of clinically relevant peptides and APOA1-containing, synthetic reconstituted HDL (rHDL) preparations that mimic the functions of full-length APOA1.
Summary
APOA1 is a multifunctional apolipoprotein that has therapeutic potential in several diseases. Translation of this knowledge into the clinic is likely to be dependent on the efficacy and bioavailability of small peptides and synthetic rHDL preparations that are currently under investigation, or in development.
Abstract The metabolic properties of the endocrine fibroblast growth factor 21 (FGF21) have been extensively studied in the past decade. Previous studies have demonstrated the lipid-lowering, ...anti-inflammatory and anti-oxidant properties of FGF21. FGF21 is mainly secreted in the liver and adipose tissue in response to a range of physiological and pathological stimuli. In animal and in vitro studies, FGF21 has been shown to improve lipid profiles and inhibit key processes in the pathogenesis of atherosclerosis. It exerts its effects on the cardiovascular system via adiponectin dependent and independent mechanisms. However, the signalling pathways by which FGF21 exerts its effects on endothelial cells remains unknown and need to be further investigated. The elevation of circulating FGF21 levels in cardiovascular disease has also raised questions as to whether FGF21 can be used as a biomarker to predict subclinical atherosclerosis and cardiovascular events. Recent findings from population studies must be validated in independent cohorts before FGF21 can be used as a biomarker in the clinical setting. The anti-atherosclerotic effects of FGF21 have been investigated in two recent clinical trials, where treatment with an FGF21 analog significantly improved the cardiometabolic profile in obese patients with type 2 diabetes. This review will evaluate recent advances that suggest there may be a role for FGF21 in atherosclerosis.
Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. ...The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin-independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.
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