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.
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.
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.
High Density Lipoproteins and Diabetes Cochran, Blake J; Ong, Kwok-Leung; Manandhar, Bikash ...
Cells (Basel, Switzerland),
04/2021, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Epidemiological studies have established that a high plasma high density lipoprotein cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent randomised clinical ...trials of interventions that increase HDL-C levels have failed to establish a causal basis for this relationship. This has led to a shift in HDL research efforts towards developing strategies that improve the cardioprotective functions of HDLs, rather than simply increasing HDL-C levels. These efforts are also leading to the discovery of novel HDL functions that are unrelated to cardiovascular disease. One of the most recently identified functions of HDLs is their potent antidiabetic properties. The antidiabetic functions of HDLs, and recent key advances in this area are the subject of this review. Given that all forms of diabetes are increasing at an alarming rate globally, there is a clear unmet need to identify and develop new approaches that will complement existing therapies and reduce disease progression as well as reverse established disease. Exploration of a potential role for HDLs and their constituent lipids and apolipoproteins in this area is clearly warranted. This review highlights focus areas that have yet to be investigated and potential strategies for exploiting the antidiabetic functions of HDLs.
Metabolic disorders are associated with an increased risk of cardiovascular disease (CVD), and are commonly characterized by a low plasma level of high-density lipoprotein cholesterol (HDL-C). ...Although cholesterol lowering medications reduce CVD risk in these patients, they often remain at increased risk of CVD. Therapeutic strategies that raise HDL-C levels and improve HDL function are a potential treatment option for reducing residual CVD risk in these individuals. Over the past decade, understanding of the metabolism and cardioprotective functions of HDLs has improved, with preclinical and clinical studies both indicating that the ability of HDLs to mediate reverse cholesterol transport, inhibit inflammation and reduce oxidation is impaired in metabolic disorders. These cardioprotective effects of HDLs are supported by the outcomes of epidemiological, cell and animal studies, but have not been confirmed in several recent clinical outcome trials of HDL-raising agents. Recent studies suggest that HDL function may be clinically more important than plasma levels of HDL-C. However, at least some of the cardioprotective functions of HDLs are lost in acute coronary syndrome and stable coronary artery disease patients. HDL dysfunction is also associated with metabolic abnormalities. This review is concerned with the impact of metabolic abnormalities, including dyslipidemia, obesity and Type 2 diabetes, on the metabolism and cardioprotective functions of HDLs.
Fibroblast growth factor 21 is a signalling protein involved in cell differentiation, morphogenesis, proliferation and metabolism. Recent studies have associated increased levels of FGF21 in the ...development of cardiovascular diseases, whereas others have reported no significant associations. Therefore, this systematic review and meta-analysis evaluated the value in predicting the risk of cardio-metabolic disorders and mortality.
PubMed and EMBASE were searched until 5th September 2017 for studies that evaluated the roles of FGF21 levels in cardio-metabolic disorders.
A total of 183 and 301 entries were retrieved; 24 studies met the inclusion criteria. Four studies were identified by an additional search. Therefore, 28 studies were included in the final meta-analysis. High FGF21 levels significantly predicted the incidence of coronary artery disease (hazard ratio HR: 1.29; 95% confidence interval CI: 1.06–1.55; P < 0. 01; I2 = 48%) and the risk of metabolic syndrome (HR: 1.70, 95% CI: 1.35–2.15; P < 0.0001 I2 = 24%). In diabetes mellitus, FGF21 predicted disease incidence or progression (HR: 1.35, 95% CI: 1.06–1.72, P < 0.05, I2 = 69%) and worsening renal failure (HR: 1.06, 95% CI: 1.03–1.09, P < 0.0001, I2 = 47%). FGF21 also predicted all-cause mortality (HR: 3.00, 95% CI: 1.23–7.33; P < 0.05; I2 = 51%), and cardiovascular mortality (HR: 2.33, 95% CI: 1.08–4.99, P < 0.05, I2 = 75%).
FGF21 significantly predicts the incidence of coronary artery disease, the risks of metabolic syndrome, diabetes mellitus and renal progression in diabetes. It also predicted all-cause and cardiovascular mortality.
ObjectivesTo investigate the association between type I collagen α1 chain (COL1α1) levels and coronary artery disease (CAD) by using absolute quantification in plasma. Also, to investigate the ...correlates of COL1α1 to clinical characteristics and circulating markers of collagen metabolism.DesignLife conditions, Stress and Health (LSH) study: prospective cohort study, here with a nested case–control design.Assessing Platelet Activity in Coronary Heart Disease (APACHE) study: prospective cohort study.SettingLSH: primary care setting, southeast Sweden.APACHE: cardiology department, university hospital, southeast Sweden.ParticipantsLSH: 1007 randomly recruited individuals aged 45–69 (50% women). Exclusion criteria was serious disease. After 13 years of follow-up, 86 cases with primary endpoint were identified and sex-matched/age-matched to 184 controls.APACHE: 125 patients with myocardial infarction (MI), 73 with ST-elevation MI and 52 with non-ST-elevation MI. Exclusion criteria: Intervention study participation, warfarin treatment and short life expectancy.Primary and secondary outcome measuresPrimary outcome was the association between baseline COL1α1 and first-time major event of CAD, defined as fatal/non-fatal MI or coronary revascularisation after 13 years. Secondary outcomes were the association between the collagen biomarkers PRO-C1 (N-terminal pro-peptide of type I collagen)/C1M (matrix metalloproteinase-mediated degradation of type I collagen) and CAD; temporal change of COL1α1 after acute MI up to 6 months and lastly, correlates between COL1α1 and patient characteristics along with circulating markers of collagen metabolism.ResultsCOL1α1 levels were associated with CAD, both unadjusted (HR=0.69, 95% CI=0.56 to 0.87) and adjusted (HR=0.55, 95% CI=0.41 to 0.75). PRO-C1 was associated with CAD, unadjusted (HR=0.62, 95% CI=0.47 to 0.82) and adjusted (HR=0.61, 95% CI=0.43 to 0.86), while C1M was not. In patients with MI, COL1α1 remained unchanged up to 6 months. COL1α1 was correlated to PRO-C1, but not to C1M.ConclusionsPlasma COL1α1 was independently and inversely associated with CAD. Furthermore, COL1α1 appeared to reflect collagen synthesis but not degradation. Future studies are needed to confirm whether COL1α1 is a clinically useful biomarker of CAD.
Abstract Objective Changes in the prevalence, treatment, and management of diabetes in the United States from 1999 to 2006 were studied using data from the National Health and Nutrition Examination ...Survey. Methods Data on 17,306 participants aged 20 years or more were analyzed. Glycemic, blood pressure, and cholesterol targets were glycosylated hemoglobin less than 7.0%, blood pressure less than 130/80 mm Hg, and low-density lipoprotein (LDL) cholesterol less than 100 mg/dL, respectively. Results The prevalence of diagnosed diabetes was 6.5% from 1999 to 2002 and 7.8% from 2003 to 2006 ( P < .05) and increased significantly in women, non-Hispanic whites, and obese people. Although there were no significant changes in the pattern of antidiabetic treatment, the age-adjusted percentage of people with diagnosed diabetes achieving glycemic and LDL targets increased from 43.1% to 57.1% ( P < .05) and from 36.1% to 46.5% ( P < .05), respectively. Glycosylated hemoglobin decreased from 7.62% to 7.15% during this period ( P < .05). The age-adjusted percentage achieving all 3 targets increased insignificantly from 7.0% to 12.2%. Conclusions The prevalence of diagnosed diabetes increased significantly from 1999 to 2006. The proportion of people with diagnosed diabetes achieving glycemic and LDL targets also increased. However, there is a need to achieve glycemic, blood pressure, and LDL targets simultaneously.
HDL maturation and remodelling Ong, Kwok-Leung; Cochran, Blake J.; Manandhar, Bikash ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
April 2022, 2022-04-00, 20220401, Letnik:
1867, Številka:
4
Journal Article
Recenzirano
Cholesterol in the circulation is mostly transported in an esterified form as a component of lipoproteins. The majority of these cholesteryl esters are produced in nascent, discoidal high density ...lipoproteins (HDLs) by the enzyme, lecithin:cholesterol acyltransferase (LCAT). Discoidal HDLs are discrete populations of particles that consist of a phospholipid bilayer, the hydrophobic acyl chains of which are shielded from the aqueous environment by apolipoproteins that also confer water solubility on the particles. The progressive LCAT-mediated accumulation of cholesteryl esters in discoidal HDLs generates the spherical HDLs that predominate in normal human plasma. Spherical HDLs contain a core of water insoluble, neutral lipids (cholesteryl esters and triglycerides) that is surrounded by a surface monolayer of phospholipids with which apolipoproteins associate. Although spherical HDLs all have the same basic structure, they are extremely diverse in size, composition, and function. This review is concerned with how the biogenesis of discoidal and spherical HDLs is regulated and the mechanistic basis of their size and compositional heterogeneity. Current understanding of the impact of this heterogeneity on the therapeutic potential of HDLs of varying size and composition is also addressed in the context of several disease states.
Detection of hypertension and blood pressure control are critically important for reducing the risk of heart attacks and strokes. We analyzed the trends in the prevalence, awareness, treatment, and ...control of hypertension in the United States in the period 1999-2004. We used the National Health and Nutrition Examination Survey 1999-2004 database. Blood pressure information on 14 653 individuals (4749 in 1999-2000, 5032 in 2001-2002, and 4872 in 2003-2004) aged >or=18 years was used. Hypertension was defined as blood pressure >or=140/90 mm Hg or taking antihypertensive medications. The prevalence of hypertension in 2003-2004 was 7.3+/-0.9%, 32.6+/-2.0%, and 66.3+/-1.8% in the 18 to 39, 40 to 59, and >or=60 age groups, respectively. The overall prevalence was 29.3%. When compared with 1999-2000, there were nonsignificant increases in the overall prevalence, awareness, and treatment rates of hypertension. The blood pressure control rate was 29.2+/-2.3% in 1999-2000 and 36.8+/-2.3% in 2003-2004. The age-adjusted increase in control rate was 8.1% (95% CI: 2.4 to 13.8%; P=0.006). The control rates increased significantly in both sexes, non-Hispanic blacks, and Mexican Americans. Among the >or=60 age group, the awareness, treatment, and control rates of hypertension had all increased significantly (P<or=0.01). The improvement in blood pressure control is encouraging, although the prevalence of hypertension has not declined.
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