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2015 ; 3
(3
): 176-192
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MOGAT2: A New Therapeutic Target for Metabolic Syndrome
#MMPMID28943619
Yang M
; Nickels JT
Diseases
2015[Aug]; 3
(3
): 176-192
PMID28943619
show ga
Metabolic syndrome is an ever-increasing health problem among the world's
population. It is a group of intertwined maladies that includes obesity,
hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and
diabetes mellitus type II (T2D). There is a direct correlation between high
triacylglycerol (triglyceride; TAG) level and severity of metabolic syndrome.
Thus, controlling the synthesis of TAG will have a great impact on overall
systemic lipid metabolism and thus metabolic syndrome progression. The Acyl-CoA:
monoacylglycerolacyltransferase (MGAT) family has three members (MGAT1, -2, and
-3) that catalyze the first step in TAG production, conversion of
monoacylglycerol (MAG) to diacylglycerol (DAG). TAG is then directly synthesized
from DAG by a Acyl-CoA: diacylglycerolacyltransferase (DGAT). The conversion of
MAG ? DAG ? TAG is the major pathway for the production of TAG in the small
intestine, and produces TAG to a lesser extent in the liver. Transgenic and
pharmacological studies in mice have demonstrated the beneficial effects of MGAT
inhibition as a therapy for treating several metabolic diseases, including
obesity, insulin resistance, T2D, and NAFLD. In this review, the significance of
several properties of MGAT physiology, including tissue expression pattern and
its relationship to overall TAG metabolism, enzymatic biochemical properties and
their effects on drug discovery, and finally what is the current knowledge about
MGAT small molecule inhibitors and their efficacy will be discussed. Overall,
this review highlights the therapeutic potential of inhibiting MGAT for lowering
TAG synthesis and whether this avenue of drug discovery warrants further clinical
investigation.