- High density lipoprotein with apolipoprotein C-III is associated with carotid intima-media thickness among generally healthy individuals. [Journal Article]
- AAtherosclerosis 2018; 269:92-99
- CONCLUSIONS: HDL apoC-III is a promising target for atherosclerosis prevention and treatment.
- Rapid Changes in Serum Lipid Profiles during Combination Therapy with Daclatasvir and Asunaprevir in Patients Infected with Hepatitis C Virus Genotype 1b. [Journal Article]
- GLGut Liver 2017 Dec 08
- CONCLUSIONS: Clearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.
- The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation. [Journal Article]
- JLJ Lipid Res 2017; 58(11):2188-2196
- Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1production under lipid-rich conditio...
Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1assembly/secretion. To test this hypothesis, we expressed C3QKin McA-RH7777 cells andapoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QKexpression increased the secretion of VLDL1-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QKcells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QKmice as compared with C3WTmice. Liver of C3QKmice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WTmice. These results suggest that C3QKvariant is a gain-of-function mutation that can stimulate VLDL1production, through enhanced DNL.
- Identification of Novel Circulating Biomarkers Predicting Rapid Decline in Renal Function in Type 2 Diabetes: The Fremantle Diabetes Study Phase II. [Journal Article]
- DCDiabetes Care 2017; 40(11):1548-1555
- CONCLUSIONS: The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes.
- A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. [Journal Article]
- NMedNat Med 2017; 23(9):1086-1094
- Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart dis...
Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
- Key differences between apoC-III regulation and expression in intestine and liver. [Journal Article]
- BBBiochem Biophys Res Commun 2017 Sep 23; 491(3):747-753
- ApoC-III is a critical cardiovascular risk factor, and humans expressing null mutations in apoC-III are robustly protected from cardiovascular disease. Because of its critical role in elevating plasm...
ApoC-III is a critical cardiovascular risk factor, and humans expressing null mutations in apoC-III are robustly protected from cardiovascular disease. Because of its critical role in elevating plasma lipids and CVD risk, hepatic apoC-III regulation has been studied at length. Considerably less is known about the factors that regulate intestinal apoC-III. In this work, we use primary murine enteroids, Caco-2 cells, and dietary studies in wild-type mice to show that intestinal apoC-III expression does not change in response to fatty acids, glucose, or insulin administration, in contrast to hepatic apoC-III. Intestinal apoC-III is not sensitive to changes in FoxO1 expression (which is itself very low in the intestine, as is FoxO1 target IGFBP-1), nor is intestinal apoC-III responsive to western diet, a significant contrast to hepatic apoC-III stimulation during western diet. These data strongly suggest that intestinal apoC-III is not a FoxO1 target and support the idea that apoC-III is not regulated coordinately with hepatic apoC-III, and establishes another key aspect of apoC-III that is unique in the intestine from the liver.
- Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study. [Journal Article]
- SStroke 2017; 48(9):2419-2425
- CONCLUSIONS: The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke.
- Association of plasminogen activator inhibitor-1 and low-density lipoprotein heterogeneity as a risk factor of atherosclerotic cardiovascular disease with triglyceride metabolic disorder: a pilot cross-sectional study. [Journal Article]
- CACoron Artery Dis 2017; 28(7):577-587
- CONCLUSIONS: The plasma PAI-1 levels may be determined by the degree of obesity and TG metabolic disorders. These factors were also shown to be correlated with a decreased LDL-particle size, increasing the risk of ASCVD, even in nondiabetic patients with well-controlled serum LDL-C levels.
- Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort. [Journal Article]
- NANeurobiol Aging 2017; 57:247.e1-247.e8
- The pathogenic relevance in Alzheimer's disease (AD) presents a decrease of cerebrospinal fluid amyloid-β42 (Aβ42) burden and an increase in cerebrospinal fluid total tau (T-tau) levels. In this work...
The pathogenic relevance in Alzheimer's disease (AD) presents a decrease of cerebrospinal fluid amyloid-β42 (Aβ42) burden and an increase in cerebrospinal fluid total tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study of T-tau/Aβ42 ratio as an AD imaging quantitative trait on 843 subjects and 563,980 single-nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain "missing heritability". Linear regression method was used to detect SNP-SNP interactions among SNPs with uncorrected p-value ≤0.01 from the GWAS. Age, gender, and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1, and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. Genome-wide interaction study revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value ≤0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Aβ42, demonstrating their potential association with AD pathology.
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- Association of apolipoprotein-CIII (apoC-III), endothelium-dependent vasodilation and peripheral neuropathy in a multi-ethnic population with type 2 diabetes. [Journal Article]
- MMetabolism 2017; 72:75-82
- CONCLUSIONS: Plasma apoC-III is higher in patients with DPN. Apart from its known association with lipids and macrovascular complications, this study suggests its association with DPN. Whether regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidemia and microvascular complications in T2D remains to be proven in future mechanistic and clinical studies.