Genetic determinants of plasma triglycerides

Johansen, Christopher T.; Kathiresan, Sekar; Hegele, Robert A.

doi:10.1194/jlr.r009720

Cited by 234 publications

(184 citation statements)

References 170 publications

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“…This is consistent with data showing that excessive fructose, but not glucose consumption, causes hypertriglyceridemia and impaired glucose metabolism in overweight human subjects (29). Fructose-induced alterations in lipid metabolism are likely in part due to activation of ChREBP and its lipogenic gene program, consistent with data showing that polymorphisms in the ChREBP locus are associated with circulating triglycerides in human populations (51,52). How activating ChREBP might participate in impaired glucose homeostasis is less obvious.…”

Section: Discussionsupporting

confidence: 80%

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Kim¹,

Krawczyk²,

Doridot³

et al. 2016

Journal of Clinical Investigation

170

185

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It has recently been hypothesized that hepatocyte CHO metabolites (hexose-or triose-phosphates) might not only stimulate ChREBP and activate DNL, but might also serve as a signal to enhance HGP (17,18). This hypothesis derives in part from the counterintuitive observation that while ChREBP is known to stimulate glycolysis through transactivation of glycolytic genes (22), it may also transactivate expression of G6pc encoding the enzyme er, from skeletal muscle and adipose tissue enhances hepatic DNL (20). Additionally, siRNA-mediated knockdown of ChREBP in ob/ob mice decreases hepatic DNL in the setting of persistent hyperinsulinemia (21). Thus, hepatic DNL may be regulated by increased substrate delivery independently of insulin signaling. However, whether increasing intrahepatic CHO metabolites might also signal to increase glucose production has not been fully explored.

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Section: Discussionsupporting

confidence: 80%

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Kim¹,

Krawczyk²,

Doridot³

et al. 2016

Journal of Clinical Investigation

170

185

View full text Add to dashboard Cite

show abstract

“…In addition, patients with severe hypertriglyceridemia can also develop pancreatitis (Athyros et al, 2002), particularly when TG levels exceed 1000-1500 mg/dl (Tsuang et al, 2009). As many as 40 different genes are now known to regulate plasma TG (Johansen et al, 2011), but only a few monogenetic disorders are known to markedly increase TG (Nordestgaard and Varbo, 2014). Rare genetic defects in lipoprotein lipase (LPL) (Benlian et al, 1996), the main enzyme responsible for the hydrolysis of TG on lipoproteins, can lead to severe hypertriglyceridemia.…”

Section: Introductionmentioning

confidence: 99%

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Sakurai¹,

Sakurai²,

Vaisman³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 6 281.2 mg/dl) and low HDL cholesterol (31.4 6 14.7 mg/dl) compared with wild-type mice (TG, 55.9 6 13.3 mg/dl; HDL cholesterol, 55.9 6 14.3 mg/dl). TGs were found in light (density , 1.063 g/ml) lipoproteins in the size range of verylow-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 mmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 6 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency.

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“…4,5 Outstanding among the genes that have been associated recently with triglyceride metabolism is the MLXIPL (Max-like protein X interacting protein-like, also known as Mondo B) that encodes the carbohydrate response element binding protein (ChREBP). In a genome-wide association study, 6 we and others reported for the first time that the MLXIPL was a new locus associated with plasma triglycerides.…”

mentioning

confidence: 99%

Amino Acid Change in the Carbohydrate Response Element Binding Protein Is Associated With Lower Triglycerides and Myocardial Infarction Incidence Depending on Level of Adherence to the Mediterranean Diet in the PREDIMED Trial

Ortega-Azorín¹,

Sorlí²,

Estruch³

et al. 2014

Circ Cardiovasc Genet

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G iven that hypertriglyceridemia is re-emerging as an important cardiovascular disease risk factor, [1][2][3] it is essential to gain further understanding about the genes involved and the environmental factors that modulate their expression. 4,5 Outstanding among the genes that have been associated recently with triglyceride metabolism is the MLXIPL (Max-like protein X interacting protein-like, also known as Mondo B) that encodes the carbohydrate response element binding protein (ChREBP). In a genome-wide association study, 6 we and others reported for the first time that the MLXIPL was a new locus associated with plasma triglycerides. We found that the minor allele of the intergenic rs17145738 polymorphism, located downstream of MLXIPL, was associated with significantly lower plasma triglyceride concentrations.6 This observation was in line with previous work in animal models in which the ChREBP, discovered by the group of Uyeda and Repa, 7 was characterized as an important transcription factor coupling hepatic glucose utilization Background-A variant (rs3812316, C771G, and Gln241His) in the MLXIPL (Max-like protein X interacting protein-like) gene encoding the carbohydrate response element binding protein has been associated with lower triglycerides. However, its association with cardiovascular diseases and gene-diet interactions modulating these traits are unknown. Methods and Results-We studied 7166 participants in the PREvención with DIeta MEDiterránea trial testing a Mediterranean diet (MedDiet) intervention versus a control diet for cardiovascular prevention, with a median follow-up of 4.8 years. Diet, lipids, MLXIPL polymorphisms, and cardiovascular events were assessed. Data were analyzed at baseline and longitudinally. We used multivariable-adjusted Cox regression to estimate hazard ratios for cardiovascular outcomes. The MLXIPL-rs3812316 was associated with lower baseline triglycerides (P=5.5×10 ) and the MedDiet intervention (P=0.030) were significantly associated with decreased triglycerides. Likewise in G-carriers MedDiet intervention was associated with greater total cardiovascular risk reduction and specifically for myocardial infarction. In the MedDiet, but not in the control group, we observed lower myocardial infarction incidence in G-carriers versus CC (hazard ratios, 0.34; 95% CI, P=0.036 and 0.90; 95% CI, P=0.830, respectively). Conclusions-Our novel results suggest that MedDiet enhances the triglyceride-lowering effect of the MLXIPL-rs3812316 variant and strengthens its protective effect on myocardial infarction incidence.

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Genetic determinants of plasma triglycerides

Cited by 234 publications

References 170 publications

ChREBP regulates fructose-induced glucose production independently of insulin signaling

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Amino Acid Change in the Carbohydrate Response Element Binding Protein Is Associated With Lower Triglycerides and Myocardial Infarction Incidence Depending on Level of Adherence to the Mediterranean Diet in the PREDIMED Trial

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