Mogat1 deletion does not ameliorate hepatic steatosis in lipodystrophic (Agpat2−/−) or obese (ob/ob) mice

Agarwal, Anil K.; Tunison, Katie; Dalal, Jasbir S.; Yen, Chi‐Liang Eric; Farese, Robert V.; Horton, Jay D.; Garg, Abhimanyu

doi:10.1194/jlr.m065896

Cited by 29 publications

(24 citation statements)

References 36 publications

(34 reference statements)

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“…There is an ongoing debate regarding the physiologic role hepatic Mogat1 plays in TAG synthesis, since it was originally thought that the glycerol-3-phosphate pathway, not the MAG pathway, is the dominant route to form TAG in the liver (Coleman and Mashek 2011; Mashek 2013). In fact one laboratory could not detect hepatic MOGAT activity (Cortes, et al 2009) and recently reported that global Mogat1 knockout in the ob/ob or Agpat2KO mice did not impact steatosis (Agarwal, et al 2016). However, hepatic MOGAT activity has been detected by other laboratories (Hall et al 2012; Yen, et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

Greenstein

Majumdar

Yang

et al. 2017

Journal of Endocrinology

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Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. Since these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18wks (Chow-fed) or after 14wks of low- or high-fat [HF] diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18wk-Chow and HF-fed mice, associated with increased NEFA after HF-feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

Greenstein

Majumdar

Yang

et al. 2017

Journal of Endocrinology

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“…The TAG that accumulates in liver of these mice is associated with increased expression of Mogat1 (encoding monoacylglycerol acyltransferase), raising the possibility that activity of this enzyme contributes to the increased TAG [94]. However, this appears not to be the case, as mice that are deficient for both Agpat2 and Mogat1 still accumulate hepatic TAG [98]. Additionally, hepatic steatosis in Agpat2 −/− mice cannot be reversed by adenoviral expression of AGPAT2 directly in liver, suggesting that steatosis does not result from local AGPAT deficiency, but rather is a secondary result of the insulin resistance that occurs due to lipodystrophy and reduced leptin levels [99,100].…”

Section: Mouse Models To Study the Physiology Of Glycerolipid Metabmentioning

confidence: 99%

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin/phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway.

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“…Strategies to suppress Mogat1 with RNAi methodology markedly improved hepatic insulin resistance (12,13) and reduced hepatic steatosis in some models (13). While recent work with whole-body Mogat1 knockout mice has questioned the contribution of this gene to tissue MGAT activity (15), acute suppression of Mogat1 expression markedly reduced MGAT activity in steatotic liver (12), suggesting chronic compensation in knockout mice.…”

mentioning

confidence: 99%

Hepatic monoacylglycerol acyltransferase 1 is induced by prolonged food deprivation to modulate the hepatic fasting response

Lutkewitte

McCommis

Schweitzer

et al. 2019

Journal of Lipid Research

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Mogat1 deletion does not ameliorate hepatic steatosis in lipodystrophic (Agpat2−/−) or obese (ob/ob) mice

Cited by 29 publications

References 36 publications

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Hepatic monoacylglycerol acyltransferase 1 is induced by prolonged food deprivation to modulate the hepatic fasting response

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