Endocrinology and Metabolism

Review Article

Diabetes, Obesity and Metabolism
Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia: Joon Ho Moon, Kyuho Kim, Sung Hee Choi; Endocrinol Metab. 2022;37(4):575-586. Published online August 29, 2022; DOI: https://doi.org/10.3803/EnM.2022.402

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High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)–lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

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Original Articles

Diabetes, Obesity and Metabolism
The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE^−/−FXR^−/− Mice: Yenna Lee, Bo-Rahm Kim, Geun-Hyung Kang, Gwan Jae Lee, Young Joo Park, Haeryoung Kim, Hak Chul Jang, Sung Hee Choi; Endocrinol Metab. 2021;36(6):1243-1253. Published online December 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1100

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Abstract PDF Supplementary Material PubReader ePub

Background
Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.
Methods
En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)^−/− and ApoE^−/−FXR^−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.
Results
Compared with ApoE^−/− mice, ApoE^−/−FXR^−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE^−/−FXR^−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).
Conclusion
Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

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Zhou Du, Junjie Hu, Lisen Lin, Qingqing Liang, Mengqi Sun, Zhiwei Sun, Junchao Duan
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Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia
Joon Ho Moon, Kyuho Kim, Sung Hee Choi
Endocrinology and Metabolism.2022; 37(4): 575. CrossRef
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Clinical Study
Apolipoprotein B Levels Predict Future Development of Hypertension Independent of Visceral Adiposity and Insulin Sensitivity: Seung Jin Han, Wilfred Y. Fujimoto, Steven E. Kahn, Donna L. Leonetti, Edward J. Boyko; Endocrinol Metab. 2020;35(2):351-358. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.351

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Background
High plasma apolipoprotein B (apoB) levels have been shown to be associated with hypertension, central obesity, and insulin resistance in cross-sectional research. However, it is unclear whether apoB levels predict future hypertension independent of body composition and insulin sensitivity. Therefore, we prospectively investigated whether plasma apoB concentrations independently predicted the risk of hypertension in a cohort of Japanese Americans.
Methods
A total of 233 normotensive Japanese Americans (77 men, 156 women; mean age, 46.4±11.0 years) were followed over 10 years to monitor them for the development of hypertension. Fasting plasma concentrations of apoB, glucose, and insulin were measured at baseline. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The abdominal visceral and subcutaneous fat areas were measured at baseline using computed tomography. Logistic regression analysis was used to estimate the association between apoB concentrations and the odds of incident hypertension.
Results
The 10-year cumulative incidence of hypertension was 21.5%. The baseline apoB level was found to be positively associated with the odds of incident hypertension over 10 years after adjustment for age, sex, body mass index, systolic blood pressure, abdominal visceral fat area, abdominal subcutaneous fat area, total plasma cholesterol concentration, diabetes status, and HOMA-IR at baseline (odds ratio and 95% confidence interval for a 1-standard deviation increase, 1.89 [1.06 to 3.37]; P=0.030).
Conclusion
Higher apoB concentrations predicted greater risks of future hypertension independent of abdominal visceral fat area and insulin sensitivity in Japanese Americans.

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Apolipoprotein B Displays Superior Predictive Value Than Other Lipids for Long-Term Prognosis in Coronary Atherosclerosis Patients and Particular Subpopulations: A Retrospective Study
Chunyan Zhang, Jingwei Ni, Zhenyue Chen
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APOA5 Polymorphism Is Associated with Metabolic Syndrome in Korean Postmenopausal Women.: Doh Hee Kim, Seung Hee Lee, Kyung Hoon Han, Chae Bong Kim, Kwan Young Song, Sook Cho, Kye Heui Lee; Endocrinol Metab. 2012;27(4):276-281. Published online December 20, 2012; DOI: https://doi.org/10.3803/EnM.2012.27.4.276

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Abstract PDF

BACKGROUND
Menopause is an independent risk factor in metabolic syndrome which induced an alteration of the lipid metabolism by hormonal changes. Apolipoprotein A5 gene (APOA5) was related to the regulation of triglyceride and high density lipoprotein cholesterol (HDL-C) level with biosynthesis and decomposition. This study was conducted to investigate the relationship between APOA5 polymorphism and metabolic syndrome in Korean postmenopausal women. METHODS: This study included 307 postmenopausal women with anthropometric and biochemical measurement in 2010-2011. The polymorphism of APOA5 was analyzed by polymerase chain reaction-restriction fragment length polymorphism method with MseI restriction enzyme. RESULTS: The metabolic syndrome prevalence with TT genotype was significantly lower than the frequency in those with TC/CC (27.09%, 38.46%, and 45.71% for TT, TC, and CC, respectively; P < 0.05). Multiple regression analysis of metabolic syndrome risk factors indicated that postmenopausal women with CC genotype had a higher risk with 3 times than that in TT genotype (P < 0.05). APOA5 C carriers showed an increased risk of triglyceride level (odd ratio, 2.93 and 1.85 for CC and TC+CC, respectively; P < 0.05). Interestingly, HDL-C was related to triglyceride directly in comparison to APOA5. CONCLUSION: The results of this study indicate that APOA5 has an influence on serum triglyceride and HDL-C, which contribute to metabolic syndrome in Korean postmenopausal women.

Citations

Citations to this article as recorded by

Effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein A-V levels in patients with impaired fasting glucose or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism
Minjoo Kim, Jey Sook Chae, Miri Kim, Sang-Hyun Lee, Jong Ho Lee
Nutrition Journal.2014;[Epub] CrossRef
APOA5Polymorphism Is Associated with Metabolic Syndrome in Korean Postmenopausal Women
Mi Hae Seo, Won Young Lee
Endocrinology and Metabolism.2012; 27(4): 274. CrossRef

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