Nuclear receptor PPARγ-regulated monoacylglycerol
            <i>O</i>
            -acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis

Lee, Yoo Jeong; Ko, Eun Hee; Kim, Ji Eun; Kim, Eunha; Lee, Hyemin; Choi, Hong-Seok; Yu, Jung Hwan; Kim, Hyo Jung; Seong, Je Kyung; Kim, Kyung‐Sup; Kim, Jae-Woo

doi:10.1073/pnas.1203218109

Cited by 148 publications

(183 citation statements)

References 29 publications

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“…This decrease in hepatic steatosis was associated with a decrease in the expression of PPARg and MGAT1. PPARg is a transcriptional factor that participates in hepatic steatosis in rodents (40,41), and PPARg-regulated MGAT1 expression has been described as responsible for lipid accumulation in diet-induced hepatic steatosis (31). SREBP1 and GK expression were downregulated in the HFD-fed PTG OE group.…”

Section: Discussionmentioning

confidence: 96%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE ), which results in an increase in liver glycogen. When fed a high-fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG OE mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG OE animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and b-hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.Liver glycogen acts as an energy store in times of nutritional sufficiency for use in times of need. The metabolism of this polysaccharide in the liver is controlled by the activities of two key enzymes: glycogen synthase (GS) and glycogen phosphorylase (GP) (1). GS is phosphorylated at multiple sites, which induces its inactivation, whereas GP is activated by phosphorylation at a single site. Both enzymes are also regulated allosterically (2,3).Glycogen-targeting subunits bind to glycogen and protein phosphatase 1 (PP1) and facilitate the dephosphorylation of GS and GP, thus activating the former and inactivating the latter. Six genes encode glycogen-targeting subunits (4). Among these, protein targeting to glycogen (PTG) (PPP1R3C or PPP1R5), which is expressed in many tissues, has been shown to control glycogen stores in various animal models (5-7).Adenoviral PTG overexpression in the liver of normal rats increases glycogen and improves glucose tolerance without perturbing lipid metabolism (8). In a diabeticfocused approach, Yang and Newgard (9) showed that adenoviral expression of PTG in the liver of STZ-diabetic rats increased glycogen content and reversed hyperglycemia and hyperphagia. Through a different approach, we reported that hepatic adenoviral expression of an active form of liver GS (LGS), which also increases glycogen content, in STZ-diabetic rats reduced food intake and hyperglycemia (10).Russek (11) was the first to propose a hepatostatic theory of food intake, which was further redefined as a glycogenostatic model by Flatt (12). This model predicts that individuals consume food to a level that maintains glycogen levels in the body (12). In fact, many lines of experimental evidence establish a correlation between the size of liver ...

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Section: Discussionmentioning

confidence: 96%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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“…Unlike the pattern observed in G0s2-knockdown 3T3-L1 cells, G0s2-knockout MEF cells accumulate many small lipid droplets during adipogenesis, but these do not mature into the larger lipid droplets observed in wild-type MEFs. Immunoblot analysis of adipocytes at days 6, 9, and 12 revealed that, to some extent, expression levels of PPARg and its regulatory genes, aP2/422, and fatspecific protein 27 21 were reduced in G0s2-knockout MEFs (Figure 7b). The reason why MEFs from G0s2-knockout mice do not exhibit increased caspase 3, as seen in 3T3-L1 cells, is not clear.…”

Section: Role Of G0s2 In Adipogenesis H Choi Et Almentioning

confidence: 99%

G0/G1 switch gene 2 has a critical role in adipocyte differentiation

Choi

Kim

et al. 2014

Cell Death Differ

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Mouse 3T3-L1 preadipocytes differentiate into adipocytes when treated with 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. Although mechanisms of adipogenesis, including transcriptional cascades, are understood, it is still unclear how clonally expanded cells eventually enter the terminal differentiation program. From gene expression profile studies, we identified G0/G1 switch gene 2 (G0s2) as a novel regulator of adipogenesis. The gene was found to be expressed at a higher level in white and brown adipose tissues, and it was induced in 3T3-L1 cells by hormonal treatment. Importantly, G0s2 expression was closely associated with the transition from mitotic clonal expansion to terminal differentiation. Knockdown of G0s2 expression with siRNA inhibited adipocyte differentiation, whereas constitutive overexpression of G0s2 accelerated differentiation of preadipocytes to mature adipocytes. Expression of G0s2 was found to be regulated by peroxisome proliferator-activated receptor c (PPARc), which is a well-known regulator of adipocyte differentiation. Absence of either PPARc or G0s2 expression resulted in apoptotic pathway activation before terminal differentiation. To determine whether G0s2 has a role in vivo, G0s2-knockout mice were generated. The knockout mice were normal in appearance, but they had less adipose mass than wild-type littermates. Mouse embryonic fibroblast cells from G0s2-deficient mice exhibited impaired adipogenesis and contained unusually small intracellular lipid droplets, suggesting that G0s2 has a role in lipid droplet formation. Our studies demonstrate that G0s2 has an important role in adipogenesis and accumulation of triacylglycerol.

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“…FAT/CD36, primarily expressed in adipose tissue, is a membrane-bound translocase that facilitates FFA uptake into the cell via diffusion and intracellular trafficking (Abumrad et al 1993). Although FAT/CD36 expression level is typically low in hepatocytes, it is increased with diet-induced obesity (Lee et al 2012). Additionally, hepatic steatosis is largely abolished in CD36 knockout mice (Zhou et al 2008), suggesting that aberrant expression of CD36, along with the resulting increase in FFA uptake in liver, may promote development or increase the severity of hepatic steatosis.…”

Section: Fatty Acid Uptakementioning

confidence: 99%

“…With a high-fat diet, PPARγ transcription is upregulated, resulting in the induction of FABP and CD36 genes and increased fatty acid uptake. Moreover, hepatic PPARγ stimulates the expression of genes involved in TG synthesis, including MGAT1, adipose differentiationrelated protein (ADRP), and fat specific protein 27 (FSP27; Lee et al 2012). Liver-specific disruption of PPARγ or MGAT1 in ob/ob mice improves fatty liver Lee et al 2012;Hasenfuss et al 2014), strongly suggesting that PPARγ and its regulatory pathway is responsible for diet-induced hepatic steatosis.…”

Section: Pparγ and Lipid Signalingmentioning

confidence: 99%

“…It is uncertain how much MAGs are directly transported into hepatocytes. In this regard, it is surprising that adenovirus-mediated MGAT1 suppression dramatically improves hepatic steatosis associated with diet-induced obesity (Lee et al 2012). MGAT1 expression is induced by peroxisome proliferator-activated receptor (PPAR)γ, which is aberrantly overexpressed in steatotic liver.…”

Section: Tg Synthesismentioning

confidence: 99%

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New mechanisms contributing to hepatic steatosis: glucose, insulin, and lipid signaling

Lee

Kim

et al. 2014

Animal Cells and Systems

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Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease and can lead to hepatic cirrhosis with liver failure. NAFLD is common in individuals who have obesity, diabetes, dyslipidemia, and/or hypertension. NAFLD comprises a wide spectrum of liver lesions ranging from mild hepatic steatosis to nonalcoholic steatohepatitis (NASH), the most aggressive form. Hepatic steatosis, also called fatty liver, is the hallmark of NAFLD and is defined as excess intrahepatic triglyceride (TG) content (≥5% of liver volume or weight). In some cases, the fat accumulation is associated with steatohepatitis, inflammation, and fibrous change of the liver. Studies on the regulation of de novo fatty acid synthesis have revealed the mechanism leading to hepatic steatosis, mostly emphasizing the roles of transcriptional regulation of enzymes involved in lipid metabolic pathway. Recently, high-fat diet-induced hepatic lipid accumulation has also been associated with hepatocyte uptake of fatty acids from lipolyzed TG in adipose tissue, as well as hepatic TG incorporation. This review discusses a conceptual framework of how hepatic TG accumulation contributes to hepatic steatosis.

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Nuclear receptor PPARγ-regulated monoacylglycerol O -acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis

Cited by 148 publications

References 29 publications

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

G0/G1 switch gene 2 has a critical role in adipocyte differentiation

New mechanisms contributing to hepatic steatosis: glucose, insulin, and lipid signaling

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