Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity

Raposo, Helena Fonseca; Forsythe, P.; Chausse, Bruno; Castelli, Júlia Zago; Moraes‐Vieira, Pedro M.; Nunes, V.S.; Oliveira, Helena Coutinho Franco de

doi:10.1016/j.metabol.2020.154429

Cited by 14 publications

(15 citation statements)

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“…Our results for the improvement of insulin sensitivity during a chronic HFD feeding demonstrate the significance of using the huCETP mouse model, which likely has more physiologically relevant levels of CETP to study the physiological roles of CETP. Raposo et al (2021) recently demonstrated that CETP expression attenuates adiposity in both huCETP and sCETP transgenic mice by enhancing lipolysis and energy expenditure. In clinic, blood CETP mass and activity are increased with obesity in non-diabetic humans ( Arai et al, 1994 ; Magkos et al, 2009 ) and the reduced expression of CETP is associated with the development of type II diabetes in obese subjects ( Kahri et al, 1994 ; MacLean et al, 2000 , 2005 ).…”

Section: Discussionmentioning

confidence: 99%

“…CETP transgenic mice have been used to study CETP-related biology since mice naturally lack CETP expression ( Marotti et al, 1993 ; Cappel et al, 2013 ; Palmisano et al, 2017 ; Raposo et al, 2021 ). Similar to observations in human studies, the impact of transgenic CETP expression in mice with regard to atherosclerosis risk factors is not consistent.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of CETP in mice carrying the human CETP minigene directs cholesterol elimination away from the intestinal pathway toward the biliary pathway during high-fat high-cholesterol feeding ( Li et al, 2019 ). Recent studies have shown a novel role of CETP to attenuate adiposity by enhancing lipolysis and brown adipose tissue activity ( Raposo et al, 2021 ). Pharmacological inhibition of CETP in transgenic mice improves HDL function with regard to cholesterol efflux and anti-oxidative capacities but worsens the anti-inflammatory capacity of HDL and decreases insulin sensitivity during a high-fat diet (HFD) feeding ( Zhu et al, 2018a ).…”

Section: Introductionmentioning

confidence: 99%

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Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

Zhu

Sivaprakasam

et al. 2022

Front. Physiol.

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Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with 3H-glucose tracer techniques. While high-fat diet feeding induced obesity for huCETP mice and their wild-type littermates lacking CETP expression, insulin sensitivity was higher for female huCETP mice than for their wild-type littermates. There was no difference in insulin sensitivity for male huCETP mice vs. littermates. The increased insulin sensitivity in females was largely caused by the better insulin-mediated suppression of hepatic glucose production. In huCETP females, CETP in the circulation decreased HDL-cholesterol content and increased liver cholesterol uptake and liver cholesterol and oxysterol contents, which was associated with the upregulation of LXR target genes in long-chain polyunsaturated fatty acid biosynthesis and PPARα target genes in fatty acid β-oxidation in the liver. The upregulated fatty acid β-oxidation may account for the improved fatty liver and liver insulin action in female huCETP mice. This study provides further evidence that CETP has beneficial physiological roles in the metabolic adaptation to nutrient excess by promoting liver fatty acid oxidation and hepatic insulin sensitivity, particularly for females.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

Zhu

Sivaprakasam

et al. 2022

Front. Physiol.

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“…In addition, hypertriglyceridemic apo C-III transgenic mice displayed enhanced whole body metabolic rate [66]. Finally, expression of CETP in transgenic mice reduced WAT mass and enhanced BAT activation [67].…”

Section: High-density Lipoprotein and Energy Expenditurementioning

confidence: 99%

Sweet swell of burning fat: emerging role of high-density lipoprotein in energy homeostasis

Kontush,

Martin,

Brites

2023

Current Opinion in Lipidology

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Purpose of review Metabolism of lipids and lipoproteins, including high-density lipoprotein (HDL), plays a central role in energy homeostasis. Mechanisms underlying the relationship between energy homeostasis and HDL however remain poorly studied. Recent findings Available evidence reveals that HDL is implicated in energy homeostasis. Circulating high-density lipoprotein-cholesterol (HDL-C) levels are affected by energy production, raising with increasing resting metabolic rate. Lipolysis of triglycerides as a source of energy decreases plasma levels of remnant cholesterol, increases levels of HDL-C, and can be cardioprotective. Switch to preferential energy production from carbohydrates exerts opposite effects. Summary Low HDL-C may represent a biomarker of inefficient energy production from fats. HDL-C-raising can be beneficial when it reflects enhanced energy production from burning fat.

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“…Consistent with a role for CETP in adipocyte lipid storage, several studies in animals have shown an association between increased FL‐CETP expression and decreased adiposity. Human CETP transgenic mice have reduced adiposity, whereas inhibition of CETP in hamsters increased their adiposity (Raposo et al, 2021). Similarly, mice with adipose tissue‐specific human CETP expression develop smaller adipocytes containing less TAG and cholesterol and reduced expression of key lipogenic genes (Zhou et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Both full length‐cholesteryl ester transfer protein and exon 9‐deleted cholesteryl ester transfer protein promote triacylglycerol storage in cultured hepatocytes

Liu

Mihna

Izem

et al. 2021

Lipids

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We previously reported that overexpression of full‐length cholesteryl ester transfer protein (FL‐CETP), but not its exon 9‐deleted variant (∆E9‐CETP), in an adipose cell line reduces their triacylglycerol (TAG) content. This provided mechanistic insight into several in vivo studies where FL‐CETP levels are inversely correlated with adiposity. However, increased FL‐CETP is also associated with elevated hepatic lipids, suggesting that the effect of CETP on cellular lipid metabolism may be tissue‐specific. Here, we directly investigated the role of FL‐CETP and ∆E9‐CETP in hepatic lipid metabolism. FL‐ or ∆E9‐CETP was overexpressed in HepG2‐C3A by adenovirus transduction. Overexpression of either FL or ∆E9‐CETP in hepatocytes increased cellular TAG mass by 25% but reduced TAG secretion. This cellular TAG was contained in larger and more numerous lipid droplets. Analysis of TAG synthetic and catabolic pathways showed that this elevated TAG content was due to increased incorporation of fatty acid into TAG (24%), and higher de novo synthesis of fatty acid (50%) and TAG from acetate (40%). siRNA knockdown of CETP had the opposite effect on TAG synthesis and lipogenesis, and decreased cellular TAG. This novel increase in cellular TAG by FL‐CETP overexpression was reproduced in Caco‐2 intestinal epithelial cells. We conclude that, unlike that seen in adipocyte cells, overexpression of either CETP isoform in lipoprotein‐secreting cells promotes the accumulation of TAG. These data suggest that the in vivo correlation between CETP levels and hepatic steatosis can be explained, in part, by a direct effect of CETP on hepatocyte cellular metabolism.

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Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity

Cited by 14 publications

References 64 publications

Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

Sweet swell of burning fat: emerging role of high-density lipoprotein in energy homeostasis

Both full length‐cholesteryl ester transfer protein and exon 9‐deleted cholesteryl ester transfer protein promote triacylglycerol storage in cultured hepatocytes

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