Diacylglycerol acyltransferase 1 inhibition with <scp>AZD7687</scp> alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial

Denison, Hans; Nilsson, Carin; Löfgren, Lars; Himmelmänn, Anders; Mårtensson, G; Knutsson, Mikael; Al‐Shurbaji, Ayman; Törnqvist, Hans; Eriksson, Jan W.

doi:10.1111/dom.12221

Cited by 90 publications

(85 citation statements)

References 37 publications

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“…DGAT1 is abundantly expressed in the small intestine (110). DGAT1 inhibition reduced postprandial TG plasma excursion in humans; however, this was accompanied by gastrointestinal side effects (111). Other DGAT1 inhibitor compounds are being developed, with the hope of satisfactory efficacy, safety, and tolerability (112).…”

Section: Diacylglycerol Acyltransferase and Monoacylglycerol Acyltranmentioning

confidence: 99%

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives in Diabetes article, we emphasize that changing demographics and lifestyles over the past few decades have resulted in an epidemic of the "atherogenic dyslipidemia complex," the main features of which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in LDL particles, accumulation of remnant lipoproteins, and postprandial hyperlipidemia. We briefly review the underlying pathophysiology of this form of dyslipidemia, in particular its association with insulin resistance, obesity, and type 2 diabetes, and the marked atherogenicity of this condition. We explain the failure of existing classes of therapeutic agents such as fibrates, niacin, and cholesteryl ester transfer protein inhibitors that are known to modify components of the atherogenic dyslipidemia complex. Finally, we discuss targeted repurposing of existing therapies and review promising new therapeutic strategies to modify the atherogenic dyslipidemia complex. We postulate that targeting the central abnormality of the atherogenic dyslipidemia complex, the elevation of triglyceriderich lipoprotein particles, represents a new frontier in CVD prevention and is likely to prove the most effective strategy in correcting most aspects of the atherogenic dyslipidemia complex, thereby preventing CVD events.

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Section: Diacylglycerol Acyltransferase and Monoacylglycerol Acyltranmentioning

confidence: 99%

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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“…Unlike mice, humans do not express DGAT2 in the intestine (41). Inhibiting the only DGAT enzyme in human intestine may block TAG synthesis completely and lead to side effects with gastrointestinal distress and malabsorption as observed in patients with a null mutation in the DGAT1 gene and in some clinical trials of DGAT1 inhibitors (42,43). Conversely, inhibiting human MGAT2 is less likely to block TAG synthesis to the same extent as the alternative glycerol-3-phosphate acyltransferase pathway is intact in humans.…”

Section: Mogat2mentioning

confidence: 99%

Intestine-specific Deletion of Acyl-CoA:Monoacylglycerol Acyltransferase (MGAT) 2 Protects Mice from Diet-induced Obesity and Glucose Intolerance

Nelson¹,

Gao²,

Yen

et al. 2014

Journal of Biological Chemistry

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Background: Global MGAT2 knock-out mice are protected from obesity. Results: Intestine-specific MGAT2 knock-out mice showed increased energy expenditure and were protected against excess weight gain and metabolic disorders induced by high fat feeding. Conclusion: Intestinal triacylglycerol metabolism is crucial in regulating systemic energy balance. Significance: Intestinal MGAT2 may be a feasible intervention target for diseases associated with excess caloric intake.

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“…DGAT1 deficient mice are also resistant to high fat diet-induced obesity (70,71), while ASO silencing of DGAT2 results in reduced liver TAGs levels (72). Targeting DGAT1 has met with some difficulty due to severe gastrointestinal side effects (73)(74)(75), while targeting DGAT2 has been gaining traction (76). Whether it is feasible to target ARV1 inhibition for treating MetS awaits further investigation into defining its molecular function.…”

Section: Arv1mentioning

confidence: 99%

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

Gallo-Ebert¹,

Francisco²,

Liu³

et al. 2018

Journal of Biological Chemistry

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Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial

Cited by 90 publications

References 37 publications

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Intestine-specific Deletion of Acyl-CoA:Monoacylglycerol Acyltransferase (MGAT) 2 Protects Mice from Diet-induced Obesity and Glucose Intolerance

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

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