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LDL disposal: Receptor vs non-receptor
Intracellular regulation of lipoprotein receptors
HEPATIC SMLR1 ABLATION FULLY PROTECTS AGAINST DIET-INDUCED ATHEROSCLEROSIS BUT CAUSES HEPATOSTEATOSIS VIA REDUCED VLDL SECRETION.
Abstract
Background and Aims
Graphical abstract
VLDL biogenesis is incompletely understood but relevant to patients with dyslipidaemia and hepatosteatosis. Over the last few years, apoB-lipoprotein synthesis is gaining significant attention. We identified SMLR1, encoding for small leucine-rich protein 1, through co-expression analyses with MTTP in human transcriptome datasets and here show that SMLR1 plays a pivotal role in lipid homeostasis.
Methods
Using somatic CRISPR/Cas9 gene editing, we downregulated hepatic Smlr1 expression in C57BL/6J male mice (Smlr1-LKD) fed a chow (8wks) or high fat (60%) high cholesterol (0.25%) diet (HFD) (12wks). Mice on HFD received AAV8-PCSK9 GoF mutation to blunt LDLR expression. H&E staining of the heart was analysed for plaque formation and a pathologist determined NAFLD activity scores. Ex vivo MTTP activity was measured with a triglyceride transfer activity assay. Immunofluorescence studies were performed in IHH cells.
Results
We show that loss of hepatic SMLR1 causes hepatosteatosis, and in line with 82% lower cholesterol and 88% lower plasma triglyceride levels, fully protects against diet-induced atherosclerosis compared to controls (p<0.001). Reduced plasma apoB (40%) and triglycerides (52%) levels in Smlr1-LKD mice on chow did not affect MTTP activity while our immunofluorescence studies show that SMLR1 is located in the ER membrane and Cis-Golgi.
Conclusions
This study shows that the transcriptome is a useful source to identify novel lipid genes. We here show that hepatic ablation of SMLR1 induces NASH but prevents atherosclerosis in mice, and propose a role for SMLR1 in VLDL trafficking form the ER to the Cis-Golgi.
THE GENETIC LACK OF ANGTPL3 DOES NOT ALTER HDL FUNCTIONALITY
Abstract
Background and Aims
Individuals with loss-of-function (LOF) mutations in ANGPTL3 gene express a unique lipid phenotype characterized by a comprehensive reduction of ApoB and Apo-AI -containing lipoproteins (so called Familial Combined Hypolipidemia or FHBL2). ANGPTL3 modulates lipoprotein metabolism by suppressing LPL and EL activity. The effect of lack of ANGTPL3 on HDL is poorly explored.
In this work, we investigated the structure and function of HDL particles in an Italian cohort of FHBL2 carriers.
Methods
Fifteen carriers of ANGPTL3 LOF mutations (5 homozygotes and 10 heterozygotes) and 10 non-affected family members (Controls) were considered. HDLs were purified by sequential ultracentrifugation from serum and analyzed for subclasses composition. Furthermore, the ability of isolated HDL to modulate the release of nitric oxide (NO) and the expression of adhesion molecules was evaluated in cultured endothelial cells.
Results
ANGPTL3 deficiency alters HDL subclass distribution. Compared with Controls, Homozygotes shown a reduced content of large HDL particles and an increased content of small particles with no alteration in HDL2 and HDL3 size. The plasma content of preβ-HDL, drastically reduced in homozygous carriers, was positively correlated with the plasma levels of ANGPTL3. Moreover, as compared with control, the capacity of HDL isolated from homozygotes to promote NO production as well as to suppress the expression of the adhesion molecules in endothelial cells were preserved.
Conclusions
These results indicated that the reduction of HDL-C level and the alteration of HDL subclass distribution observed in subjects with genetically determined ANGPTL3 deficiency does not hamper the vaso-protective and the anti-inflammatory properties of this lipoprotein fraction
LDL-CHOLESTEROL LEVELS AND LDL POLYGENIC SCORE IN A COHORT OF PATIENTS WITH CLINICALLY DIAGNOSED FAMILIAL HYPERCHOLESTEROLEMIA. DATA FROM THE LIPIGEN STUDY
Abstract
Background and Aims
Polygenic hypercholesterolemia has been suggested to explain the significant proportion of patients with a diagnosis of familial hypercholesterolemia (FH) based on clinical and biochemical criteria, but without any disease-causing mutation.
Methods
We evaluated the distribution of a polygenic risk score proposed by Talmud et al. (Lancet, 2013), consisting of 12 LDL cholesterol (LDL-C) raising variants (LDLc-score), in a large Italian population of adult patients diagnosed with clinical FH
Results
Within the LIPIGEN study, 875 mutation-positive (FH/M+) patients (females 54.75%, mean age 42.47±15.00 years) and 644 mutation-negative (FH/M-) patients (females 54.21%, mean age 49.73±13.54 years) were evaluated. FH/M- patients had lower mean levels of pre-treatment LDL-C than FH/M+ group (217.14±55.49 vs 270.52±68.59 mg/dL, p<0.0001). The mean value (±SD) of the LDLc-score was 1.00 (±0.18) in FH/M- patients and 0.94 (±0.20) in FH/M+ group (p-value <0.0001). Higher mean LDLc-score levels were observed among FH/M- having pre-treatment LDL-C levels in the range 150-350 mg/dL (150-249 mg/dL: 1.01 vs 0.91, p-value <.0001; 250-349 mg/dL: 1.02 vs 0.95, p-value=0.0001). A positive correlation between LDLc-score and pre-treatment LDL-C levels was observed among FH patients independently of the presence of causative mutations.
Conclusions
From these data, we suggest that variants in multiple LDL-cholesterol-raising genes can play a role in determining LDL-C levels even in patients with monogenic familial hypercholesterolemia. More data is needed to investigate the association between the polygenic score and the risk of atherosclerotic disease to support its use in clinical practice.
DO TRIGLYCERIDES HAVE AN INFLUENCE ON ENDOTHELIAL FUNCTION DETECTED BY LASER DOPPLER FLOWMETRY?
Abstract
Background and Aims
The emerging data show that lower triglyceride levels are associated with better vascular function. However, the exact cut-off value for triglycerides remains undefined. We aimed to find out whether better endothelial function is associated with lower plasma triglyceride levels in subjects with metabolic syndrome in Lithuanians.
Methods
3081 patients (1865 women and 1216 men, mean age 53±6 years) with metabolic syndrome were enrolled in the study, which was conducted during the period of 2010–2014 at Vilnius University Hospital Santaros Klinikos. Microvascular endothelial function was evaluated using the Laser Doppler flowmetry in combination with the post-occlusive reactive hyperaemia test. The percentage change of flow from peak to the rest flow (PF-RF) was calculated and used as the main measure of endothelial function.
Results
The study showed that higher PF-RF score was significantly associated with decreased triglyceride levels (p=0.002), female sex (p<0.001) and the absence of diabetes (p=0.004). There was a weak but statistically significant negative correlation between triglycerides and PF-RF both in all subjects and separately in women and in men (r=-0.08, p<0.001; r=-0.06, p=0.01; r=-0.08, p=0.01, respectively). Correspondingly, subjects with triglyceride levels <1.7 mmol/l and <1.3 mmol/l had higher PF-RF score as compared to patients with triglyceride levels ≥1.7 mmol/l and ≥1.3 mmol/l (n=1215; 377±289 vs n=1781; 341±260; p<0.001 and n=606; 389±285 vs n=2390; 347±269; p<0.001, respectively).
Conclusions
Subjects with metabolic syndrome who have lower plasma triglyceride levels have better endothelial function. Next step of this work is to show if this observation is independently related to lower cardiovascular risk in the future.
IMPORTANCE OF APOB AND NON-HDL CHOLESTEROL FOR ISCHEMIC STROKE IS DOUBLE THAT OF LDL CHOLESTEROL
Abstract
Background and Aims
Conflicting results have been reported on the association between lipids and risk of ischemic stroke. We examined the burden of ischemic stroke attributable to apolipoprotein B (apoB), non-high-density lipoprotein (non-HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol.
Methods
We included 104 618 individuals from an ongoing cohort study, the Copenhagen General Population Study. The associations of quintiles of apoB, non-HDL cholesterol, and LDL cholesterol with risk of ischemic stroke were estimated by Cox proportional hazards regressions with 95% confidence intervals. With 1st quintile as reference, the proportion of ischemic stroke attributable to the 2nd, 3rd, 4th, and 5th quintiles of apoB, non-HDL cholesterol, and LDL cholesterol were estimated by the population attributable fraction (PAF).
Results
Quintiles of apoB and non-HDL cholesterol were associated with a stepwise increased risk of ischemic stroke, whereas only the upper two quintiles of LDL cholesterol were associated with increased risk of ischemic stroke. A similar pattern was seen for PAF values. Compared to the 1st quintile, the combined proportion of ischemic stroke attributable to individuals in the 2nd to 5th quintiles of apoB (levels > 82 mg/dL), non-HDL cholesterol (levels > 3.0 mmol/L, > 117 mg/dL), and LDL cholesterol (levels > 2.4 mmol/L, > 94 mg/dL) were 17.0%, 16.0%, and 8.4%, respectively.
Conclusions
The proportion of ischemic stroke attributable to elevated apoB and non-HDL cholesterol was double that attributable to elevated LDL cholesterol, indicating that the risk of ischemic stroke is better reflected by elevated apoB and non-HDL cholesterol than elevated LDL cholesterol.