Regulation of Steatohepatitis and PPARγ Signaling by Distinct AP-1 Dimers

Hasenfuss, Sebastian C.; Bakiri, Latifa; Thomsen, Martin K.; Williams, Evan G.; Auwerx, Johan; Wagner, Erwin F.

doi:10.1016/j.cmet.2013.11.018

Cited by 101 publications

(109 citation statements)

References 59 publications

(71 reference statements)

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“…Given the ability of ChREBP-MLX to bind and activate the transcription of several lipogenic enzyme genes, the activation of ChREBP-MLX may be the glucose-dependent mechanism responsible for the synergistic induction of fatty acid synthesis by glucose and insulin [63]. Transcription factor activator protein 1 (AP1) was also upregulated in the HCBD group ( Figure 5), and increases in AP1 transcription have been linked to obesity, hepatic lipid metabolism, and NAFLD [64]. In the HCBD group, the PEPCK gene was also upregulated (Table 3).…”

Section: Discussionmentioning

confidence: 98%

Transcriptomic and Metabolomics Analyses Show that High Carbohydrate Induces Fatty Liver in Blunt Snout Bream (Megalobrama amblycephala)

Prisingkorn

Prathomya

Liu

et al. 2017

Preprint

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A high intake of carbohydrates, associated with obesity, is one of the major causes of fatty liver disease in humans.This study investigated how high carbohydrate intake induces fatty liver disease in Blunt snout bream (Megalobrama amblycephala). Blunt snout bream were fed a high-carbohydrate diet (HCBD) for 60 days. Their growth indices were evaluated, and the transcriptomes, metabolites, biochemistry, and histology of their blood and livers were analyzed. The final weight, weight gain, specific growth rate, and feed conversion ratio were all higher in the HCBD group than in the control group, but not significantly so (P > 0.05). The hepatosomatic index (HSI) differed significantly in the two groups (P < 0.05), and the metabolomics results showed that a high carbohydrate intake induced significant increases in plasma α/β-glucose, succinate, and tyrosine, which could increase hepatic glycogen and triglyceride. Low levels of betaine were also found in the livers of the HCBD group. The histology and blood biochemistry results suggested abnormal liver, with excessive lipid accumulation and liver damage. A transcriptome analysis and quantitative reverse transcription-PCR (RT-qPCR) indicated that the expression of the factors INSR, IRS, PI3K, PDK, AKT, ACC, IL6, AP1, ChREBP-MLX, PEPCK, and FBP in the insulin signaling pathway was significantly upregulated and that of SOCS3, GSK3β, and AMPK significantly downregulated in the HCBD. This pattern is associated with the nonalcoholic fatty liver disease (NAFLD) pathway. This study extends our understanding of how high carbohydrate causes increased fat deposition in the liver, enhanced glycolysis (α/β-glucose) in the plasma, and reduced betaine in the liver. This leads to activation of hepatocyte insulin resistance and lipogenesis by regulating the expression of genes related to fatty liver disease.Keyword: blunt snout bream; high carbohydrate; transcriptome; metabolomics; insulin resistance; fatty liver disease Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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Section: Discussionmentioning

confidence: 98%

Transcriptomic and Metabolomics Analyses Show that High Carbohydrate Induces Fatty Liver in Blunt Snout Bream (Megalobrama amblycephala)

Prisingkorn

Prathomya

Liu

et al. 2017

Preprint

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“…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. In this case, increased body fat stimulates lipid signaling, which triggers the expression of PPARγ (Figure 1).…”

Section: Pparγ and Lipid Signalingmentioning

confidence: 99%

“…In this regard, PPARγ has been recently emphasized as a gene that has a critical role in diet-induced hepatic steatosis. For example, PPARγ regulation by the activator protein-1 (AP-1) complex is important for the PPARγ activation in hepatic steatosis (Hasenfuss et al 2014) and repression of PPARγ target genes such as MGAT1 decreases hepatic steatosis in a high-fat fed mouse model (Lee et al 2012). Therefore, future research should investigate the role and regulation of PPARγ and its target genes in mouse and human models of hepatic steatosis.…”

Section: Future Directionmentioning

confidence: 99%

“…Because PPARγ ligands are derived from lipid metabolism (Forman et al 1995), increased lipid signaling from the diet or from lipolysis of adipose tissue may play a role in PPARγ expression or activation. PPARγ1 and γ2 promoters may also be regulated epigenetically or transcriptionally in response to lipid signaling (Hasenfuss et al 2014).…”

Section: Pparγ and Lipid Signalingmentioning

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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“…Hepatic lipid overload induces c-Jun N-terminal kinase (JNK)-mediated stress response pathway, which is often associated with the pathogenesis of NAFLD (33,34). Since c-Jun, the downstream effector of this pathway, has been implicated in the transcriptional regulation of lipoapoptosis and steatohepatitis (33,35,36), we hypothesized that c-Jun might be involved in the selective recruitment of LSD2 to lipid metabolism gene loci. In lipid metabolism gene loci, 12-O-tetradecanoylphorbol 13-acetate (TPA)-responsive elements (TREs), which harbor a c-Jun binding motif, were located near LSD2 ChIP-seq peaks ( Fig.…”

Section: Lsd2mentioning

confidence: 99%

Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells

Nonomura

Hino

Sakamoto

et al. 2015

Molecular and Cellular Biology

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dCells link environmental fluctuations, such as nutrition, to metabolic remodeling. Epigenetic factors are thought to be involved in such cellular processes, but the molecular basis remains unclear. Here we report that the lysine-specific demethylase 2 (LSD2) suppresses the flux and metabolism of lipids to maintain the energy balance in hepatic cells. Using transcriptome and chromatin immunoprecipitation-sequencing analyses, we revealed that LSD2 represses the genes involved in lipid influx and metabolism through demethylation of histone H3K4. Selective recruitment of LSD2 at lipid metabolism gene loci was mediated in part by a stress-responsive transcription factor, c-Jun. Intriguingly, LSD2 depletion increased the intracellular levels of many lipid metabolites, which was accompanied by an increased susceptibility to toxic cell damage in response to fatty acid exposure. Our data demonstrate that LSD2 maintains metabolic plasticity under fluctuating environment in hepatocytes by mediating the cross talk between the epigenome and metabolism.O rganisms and cells must adjust their energy strategy to fluctuating nutrient availability and other environmental conditions. Epigenetic mechanisms have been implicated in the phenotypic plasticity in response to environmental changes, as well as in consistent execution of the developmental program (1). It has been shown that nutrients and dietary composition potently influence epigenetic marks, including DNA methylation and histone methylation and acetylation, in both humans and animal models (2).Because chromatin-modifying enzymes utilize nutrient-derived metabolites as substrates and coenzymes, epigenome formation is, by nature, influenced by nutritional and metabolic conditions (3-6). Lysine-specific demethylases 1 and 2 (LSD1 and LSD2), also known as KDM1A and KDM1B, respectively, comprise the flavin-dependent amine oxidase family of histone demethylases (7). These enzymes require flavin adenine dinucleotide (FAD) as a coenzyme for the removal of methyl groups from the lysine residue of histone H3 and other proteins (8,9). FAD is a vitamin B 2 -derived metabolite that serves as a redox cofactor in key metabolic processes such as fatty acid oxidation and succinate dehydrogenation in the tricarboxylic acid (TCA) cycle (10). Thus, the cellular metabolic state may influence the demethylase activity of these proteins. Indeed, we and others have previously demonstrated that LSD1 controls energy metabolism genes in response to extracellular conditions (11, 12), suggesting that FAD-dependent epigenetic factors may link environmental information to metabolic programming. LSD2 was identified as a second flavin-dependent histone demethylase that targets methylated lysines 4 and 9 of histone H3 (H3K4 and H3K9, respectively) (8,(13)(14)(15). Although LSD2 has been implicated in the establishment of maternal genomic imprinting in oocytes (16), little is known about its biological functions, particularly in relation to metabolic control.In the liver, hepatocytes play a crucial role in...

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Regulation of Steatohepatitis and PPARγ Signaling by Distinct AP-1 Dimers

Cited by 101 publications

References 59 publications

Transcriptomic and Metabolomics Analyses Show that High Carbohydrate Induces Fatty Liver in Blunt Snout Bream (<em>Megalobrama amblycephala</em>)<strong></strong>

Transcriptomic and Metabolomics Analyses Show that High Carbohydrate Induces Fatty Liver in Blunt Snout Bream (<em>Megalobrama amblycephala</em>)<strong></strong>

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

Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells

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