Current Status of the Research and Development of Diacylglycerol <i>O</i>-Acyltransferase 1 (DGAT1) Inhibitors

DeVita, Robert J.; Pinto, Shirly

doi:10.1021/jm4007033

Cited by 91 publications

(76 citation statements)

References 18 publications

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“…Diacylglycerol O-acyltransferase 1 mediates the final step in triglyceride synthesis and is expressed in the small intestine, liver, adipose tissues, and the mammary gland (DeVita and Pinto, 2013;Muise et al, 2014). The pharmaceutical industry has a great interest in DGAT1 as a target for human metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

Effects of the DGAT1 polymorphism on test-day milk production traits throughout lactation

Bovenhuis

Visker

Valenberg

et al. 2015

Journal of Dairy Science

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Section: Introductionmentioning

confidence: 99%

Effects of the DGAT1 polymorphism on test-day milk production traits throughout lactation

Bovenhuis

Visker

Valenberg

et al. 2015

Journal of Dairy Science

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“…Mammalian DGAT1, on the other hand, is relevant in medicine, as it has been investigated as a drug target for a variety of lipid-related metabolic diseases, including obesity 1 and diabetes (Zammit et al, 2008;Birch et al, 2010). Many DGAT1 inhibitors have already been designed, synthesized, and tested (DeVita and Pinto, 2013). Bovine (Bos taurus) DGAT1 also is important in the cattle industry, as it is used as a polymorphic genetic marker for the fat content of milk (Winter et al, 2002;Grisart et al, 2004).…”

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confidence: 99%

Diacylglycerol Acyltransferase 1 Is Regulated by Its N-Terminal Domain in Response to Allosteric Effectors

et al. 2017

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ORCID IDs: 0000-0001-8699-690X (R.J.W.); 0000-0003-4745-9153 (M.J.L.).Diacylglycerol acyltransferase 1 (DGAT1) is an integral membrane enzyme catalyzing the final and committed step in the acylcoenzyme A (CoA)-dependent biosynthesis of triacylglycerol (TAG). The biochemical regulation of TAG assembly remains one of the least understood areas of primary metabolism to date. Here, we report that the hydrophilic N-terminal domain of Brassica napus DGAT1 (BnaDGAT1 1-113 ) regulates activity based on acyl-CoA/CoA levels. The N-terminal domain is not necessary for acyltransferase activity and is composed of an intrinsically disordered region and a folded segment. We show that the disordered region has an autoinhibitory function and a dimerization interface, which appears to mediate positive cooperativity, whereas the folded segment of the cytosolic region was found to have an allosteric site for acyl-CoA/CoA. Under increasing acyl-CoA levels, the binding of acyl-CoA with this noncatalytic site facilitates homotropic allosteric activation. Enzyme activation, on the other hand, is prevented under limiting acyl-CoA conditions (low acyl-CoA-to-CoA ratio), whereby CoA acts as a noncompetitive feedback inhibitor through interaction with the same folded segment. The three-dimensional NMR solution structure of the allosteric site revealed an a-helix with a loop connecting a coil fragment. The conserved amino acid residues in the loop interacting with CoA were identified, revealing details of this important regulatory element for allosteric regulation. Based on these results, a model is proposed illustrating the role of the N-terminal domain of BnaDGAT1 as a positive and negative modulator of TAG biosynthesis.

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“…In mice, DGAT1 is expressed in many organs, including the skeletal muscle, heart, and intestines, but it is barely expressed in the liver (5). Because DGAT1-deficient mice are resistant to diet-induced obesity (7), pharmacological DGAT1 inhibitors are being developed for the treatment of metabolic diseases (8). In contrast to mice, human DGAT1 is mainly expressed in the small intestine and liver (9).…”

mentioning

confidence: 99%

Hepatitis C Virus Entry Is Impaired by Claudin-1 Downregulation in Diacylglycerol Acyltransferase-1-Deficient Cells

Sung

Murayama

Kang

et al. 2014

J Virol

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Diacylglycerol acyltransferase-1 (DGAT1) is involved in the assembly of hepatitis C virus (HCV) by facilitating the trafficking of the HCV core protein to the lipid droplet. Here, we abrogated DGAT1 expression in Huh-7.5 cells by using either the transcription activator-like effector nuclease (TALEN) or lentivirus vector short hairpin RNA (shRNA) and achieved complete long-term silencing of DGAT1. HCV entry was severely impaired in DGAT1-silenced Huh-7.5 cell lines, which showed markedly diminished claudin-1 (CLDN1) expression. In DGAT1-silenced cell lines, the forced expression of CLDN1 restored HCV entry, implying that the downregulation of CLDN1 is a critical factor underlying defective HCV entry. The expression of the gene coding for hepatocyte nuclear factor 4␣ (HNF4␣) and other hepatocyte-specific genes was also reduced in DGAT1-silenced cell lines. After DGAT1 gene rescue, CLDN1 expression was preserved, and HCV entry was restored. Strikingly, after DGAT1 silencing, CLDN1 expression and HCV entry were also restored by low-dose palmitic acid treatment, indicating that the downregulation of CLDN1 was associated with altered fatty acid homeostasis in the absence of DGAT1. Our findings provide novel insight into the role of DGAT1 in the life cycle of HCV. IMPORTANCEIn this study, we report the novel effect of complete silencing of DGAT1 on the entry of HCV. DGAT1 was recently reported as a host factor of HCV, involved in the assembly of HCV by facilitating the trafficking of the HCV core protein to lipid droplets. We achieved complete and long-term silencing of DGAT1 by either TALEN or repeated transduction of lentivirus shRNA. We found that HCV entry was severely impaired in DGAT1-silenced cell lines. The impairment of HCV entry was caused by CLDN1 downregulation, and the expression of HNF4␣ and other hepatocyte-specific genes was also downregulated in DGAT1-silenced cell lines. Our results suggest new roles of DGAT1 in human liver-derived cells: maintaining intracellular lipid homeostasis and affecting HCV entry by modulating CLDN1 expression. H epatitis C virus (HCV) infection poses a major threat to human health, with a prevalence of more than 160 million people worldwide (1). In addition to a combination regimen of pegylated interferon alpha (IFN-␣) and ribavirin, drugs acting directly on HCV have now been developed, although these direct-acting antivirals may prompt the emergence of resistant strains (2, 3). Our increasing understanding of the HCV-host interactions is allowing novel therapeutic approaches to be developed that modulate host factors that are required for viral entry, replication, and egress; these factors may have a higher genetic barrier to viral resistance (4).Diacylglycerol acyltransferase-1 (DGAT1) is one of two known DGAT enzymes catalyzing the final step in triglyceride biosynthesis (5, 6). The expression of DGAT1 and its physiologic role differ in humans and mice. In mice, DGAT1 is expressed in many organs, including the skeletal muscle, heart, and intestines, but it is bar...

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Current Status of the Research and Development of Diacylglycerol O-Acyltransferase 1 (DGAT1) Inhibitors

Cited by 91 publications

References 18 publications

Effects of the DGAT1 polymorphism on test-day milk production traits throughout lactation

Effects of the DGAT1 polymorphism on test-day milk production traits throughout lactation

Diacylglycerol Acyltransferase 1 Is Regulated by Its N-Terminal Domain in Response to Allosteric Effectors

Hepatitis C Virus Entry Is Impaired by Claudin-1 Downregulation in Diacylglycerol Acyltransferase-1-Deficient Cells

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