CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

Zhu, Lin; Luu, Thao; Emfinger, Christopher H.; Parks, Bryan A.; Shi, Jeanne; Trefts, Elijah; Zeng, Fenghua; Kuklenyik, Zsuzsanna; Harris, Raymond C.; Wasserman, David H.; Fazio, Sergio; Stafford, John M.

doi:10.2337/db18-0474

Cited by 27 publications

(27 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study is not the first to show deleterious metabolic outcomes induced by long-term therapies designed to improve HDL concentrations or functions. Consistent with our findings, other experimental strategies (i.e., microRNA 33 (miR-33) antagonism and cholesteryl ester transfer protein (CETP) inhibition) aimed at increasing circulating HDL levels and inducing the m-RCT were also reported to exert long-term, adverse metabolic effects on obese mice [33,34,35], including increased weight gain [35], dyslipidemia [34], and steatosis [33,34].…”

Section: Discussionsupporting

confidence: 87%

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

Méndez-Lara

Farré

Santos

et al. 2019

IJMS

View full text Add to dashboard Cite

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans.

show abstract

Section: Discussionsupporting

confidence: 87%

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

Méndez-Lara

Farré

Santos

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Four microliters of serum/plasma were used for immunoblotting to quantify plasma levels of ApoC1, ApoC2, and ApoC3 with a protocol we published previously [62]. Ponceau S staining was used for normalization.…”

Section: Western Blottingmentioning

confidence: 99%

Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice

et al. 2021

Self Cite

View full text Add to dashboard Cite

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. Here, we test the hypothesis that hepatic SHP mediates sex differences in TG metabolism using hepatocyte-specific SHP knockout mice. Plasma TGs in wild-type males were higher than in wild-type females and hepatic deletion of SHP lowered plasma TGs in males but not in females, suggesting hepatic SHP mediates plasma TG metabolism in a sex-specific manner. Additionally, hepatic deletion of SHP failed to lower plasma TGs in gonadectomized male mice or in males with knockdown of the liver androgen receptor, suggesting hepatic SHP modifies plasma TG via an androgen receptor pathway. Furthermore, the TG lowering effect of hepatic deletion of SHP was caused by increased clearance of postprandial TG and accompanied with decreased plasma levels of ApoC1, an inhibitor of lipoprotein lipase activity. These data support a role for hepatic SHP in mediating sex-specific effects on plasma TG metabolism through androgen receptor signaling. Understanding how hepatic SHP regulates TG clearance may lead to novel approaches to lower plasma TGs and mitigate cardiovascular disease risk.

show abstract

“…Peptides at m / z 2847.9, 1208.52, 1764.38, 2610.06, 2847.9 and 3805.09 represent phospholipid transfer protein. Phospholipid transfer protein regulates the HDL composition and size and controls plasma HDL levels (Huuskonen, Olkkonen, Jauhiainen, & Ehnholm, ; Zhu et al, ). Apolipoprotein E maintains lipid and lipoprotein levels in the blood.…”

Section: Resultsmentioning

confidence: 99%

Enrichment of HDL proteome and phospholipidome from human serum via IMAC/MOAC affinity

Javeed

Hussain

Jabeen

et al. 2019

Biomedical Chromatography

View full text Add to dashboard Cite

High‐density lipoproteins (HDLs) have anti‐inflammatory and antioxidant properties and are potentially cardio‐protective. Defective HDL function is caused by alterations in both the proteome and lipidome of HDL particles. As potential biomarkers, the development of analytical methods is necessary for the enrichment of HDLs. Therefore, a method for selective enrichment of HDLs using immobilized metal ion affinity chromatography (IMAC) and metal oxide affinity chromatography (MOAC) is presented. SPE‐based isolation of HDLs from whole serum is adopted as an alternative to traditional ultracentrifugation methods followed by SDS–PAGE. The enrichment mechanism relies on isoelectric points of lipoproteins and metal oxide. Negatively charged lipoprotein particles interact with positively charged metal oxides and IMAC affinity, which acts as a cation. Identified proteins from HDL through MALDI–MS analysis are apo AI, AII, AIV, CI, CIII, E, J, M, H, serum amyloid A and other nonapoproteins that are part of HDL particles and perform cellular functions. This serum‐based proteomics approach gives insight into the functional role of HDL. HDL‐associated phospholipids have also been analyzed by LDI–MS. Results suggest that the adopted analytical strategy is a feasible idea to extract lipoproteins from serum. A comparative study of healthy and diseased samples using this approach will provide valuable information in future.

show abstract

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

Cited by 27 publications

References 46 publications

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice

Enrichment of HDL proteome and phospholipidome from human serum via IMAC/MOAC affinity

Contact Info

Product

Resources

About