Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

Naik, Ravi; Brice, Obiang-Obounou; Kim, Minkyoung; Choi, Yongseok; Lee, Hyun S un; Lee, Kyeong

doi:10.1002/cmdc.201402069

Cited by 37 publications

(28 citation statements)

References 104 publications

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“…In mammals, DGAT1 and DGAT2 are the two isoforms of DGATs [ 37 ]. Inhibition of either DGAT1 or DGAT2 has been considered to be an attractive target for the treatment of dyslipidemia [ 38 ]. However, the effects of DGATs on lipotoxicity remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone ameliorates palmitic acid-induced cytotoxicity in TM4 Sertoli cells

Pan

Jing

et al. 2018

Reprod Biol Endocrinol

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The Sertoli cell is the only somatic cell within the seminiferous tubules, and is vital for testis development and spermatogenesis. Rosiglitazone (RSG) is a member of the thiazolidinedione family and is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. It has been reported that RSG protects various types of cells from fatty acid-induced damage. However, whether RSG serves a protective role in Sertoli cells against palmitic acid (PA)-induced toxicity remains to be elucidated. Therefore, the aim of the present study was to investigate the effect of RSG on PA-induced cytotoxicity in Sertoli cells. MTT assay and Oil Red O staining revealed that RSG ameliorated the PA-induced decrease in TM4 cell viability, which was accompanied by an alleviation of PA-induced lipid accumulation in cells. In primary mouse Sertoli cells, RSG also showed similar protective effects against PA-induced lipotoxicity. Knockdown of PPARγ verified that RSG exerted its protective role in TM4 cells through a PPARγ-dependent pathway. To evaluate the mechanism underlying the protective role of RSG on PA-induced lipotoxicity, the present study analyzed the effects of RSG on PA uptake, and the expression of genes associated with both fatty acid oxidation and triglyceride synthesis. The results demonstrated that although RSG did not affect the endocytosis of PA, it significantly elevated the expression of carnitine palmitoyltransferase (CPT)-1A, a key enzyme involved in fatty acid oxidation, which indicated that the protective effect of RSG may have an important role in fatty acid oxidation. On the other hand, the expression of CPT1B was not affected by RSG. Moreover, the expression levels of diacylglycerol O-acyltransferase (DGAT)-1 and DGAT2, both of which encode enzymes catalyzing the synthesis of triglycerides, were not suppressed by RSG. The results indicated that RSG reduced PA-induced lipid accumulation by promoting fatty acid oxidation mediated by CPT1A. The effect of RSG in protecting cells from lipotoxicity was also found to be specific to Sertoli cells and hepatocytes, and not to other cell types that do not store excess lipid in large quantities, such as human umbilical vein endothelial cells. These findings provide insights into the cytoprotective effects of RSG on Sertoli cells and suggest that PPARγ activation may be a useful therapeutic method for the treatment of Sertoli cell dysfunction caused by dyslipidemia.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0416-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Rosiglitazone ameliorates palmitic acid-induced cytotoxicity in TM4 Sertoli cells

Pan

Jing

et al. 2018

Reprod Biol Endocrinol

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“…Altogether, the aforementioned data suggest that enhanced synthesis of TAGs in adipose tissue of obese subjects may predispose to obesity progression. Two isoforms of DGAT have been identified in the liver: DGAT1, responsible for deposition of TAGs, and DGAT2, involved in TAG secretion . Although there are no data on the expression of the DGAT gene in the liver of obese persons, recent evidence suggests that inhibitors of both DGAT isoforms may be successfully used in the treatment of human obesity and metabolic disorders, including hypertriglyceridemia and liver steatosis .…”

Section: Role Of Endogenous Lipid Synthesis As a Determinant Of Lipidmentioning

confidence: 99%

Alterations of specific lipid groups in serum of obese humans: a review

Mika

Śledziński

2016

Obesity Reviews

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Obesity is a major contributor to the dysfunction of liver, cardiac, pulmonary, endocrine and reproductive system, as well as a component of metabolic syndrome. Although development of obesity-related disorders is associated with lipid abnormalities, most previous studies dealing with the problem in question were limited to routinely determined parameters, such as serum concentrations of triacylglycerols, total cholesterol, low-density and high-density lipoprotein cholesterol. Many authors postulated to extend the scope of analysed lipid compounds and to study obesity-related alterations in other, previously non-examined groups of lipids. Comprehensive quantitative, structural and functional analysis of specific lipid groups may result in identification of new obesity-related alterations. The review summarizes available evidence of obesity-related alterations in various groups of lipids and their impact on health status of obese subjects. Further, the role of diet and endogenous lipid synthesis in the development of serum lipid alterations is discussed, along with potential application of various lipid compounds as risk markers for obesity-related comorbidities.

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“…Pancreatic lipase activity was measured as previously described (36) . In brief, FGT was dissolved in distilled water (as a negative control) or in 50 For neurotransmitter measurements, 6-week-old male C57/ BL6 mice were purchased from the Central Laboratory Animal Inc. and adapted for 1 week. After adaptation, mice were fed a 45 % HFD.…”

Section: Pancreatic Lipase Activity Assaymentioning

confidence: 99%

Fermented green tea extract exhibits hypolipidaemic effects through the inhibition of pancreatic lipase and promotion of energy expenditure

et al. 2017

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Hyperlipidaemia is a major cause of atherosclerosis and related CVD and can be prevented with natural substances. Previously, we reported that a novel Bacillus-fermented green tea (FGT) exerts anti-obesity and hypolipidaemic effects. This study further investigated the hypotriglyceridaemic and anti-obesogenic effects of FGT and its underlying mechanisms. FGT effectively inhibited pancreatic lipase activity in vitro (IC50, 0·48 mg/ml) and ameliorated postprandial lipaemia in rats (26 % reduction with 500 mg/kg FGT). In hypertriglyceridaemic hamsters, FGT administration significantly reduced plasma TAG levels. In mice, FGT administration (500 mg/kg) for 2 weeks augmented energy expenditure by 22 % through the induction of plasma serotonin, a neurotransmitter that modulates energy expenditure and mRNA expressions of lipid metabolism genes in peripheral tissues. Analysis of the gut microbiota showed that FGT reduced the proportion of the phylum Firmicutes in hamsters, which could further contribute to its anti-obesity effects. Collectively, these data demonstrate that FGT decreases plasma TAG levels via multiple mechanisms including inhibition of pancreatic lipase, augmentation of energy expenditure, induction of serotonin secretion and alteration of gut microbiota. These results suggest that FGT may be a useful natural agent for preventing hypertriglyceridaemia and obesity.

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Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

Cited by 37 publications

References 104 publications

Rosiglitazone ameliorates palmitic acid-induced cytotoxicity in TM4 Sertoli cells

Rosiglitazone ameliorates palmitic acid-induced cytotoxicity in TM4 Sertoli cells

Alterations of specific lipid groups in serum of obese humans: a review

Fermented green tea extract exhibits hypolipidaemic effects through the inhibition of pancreatic lipase and promotion of energy expenditure

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