Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis

Wang, Chenyu; Stapleton, Donald S.; Schueler, Kathryn L.; Rabaglia, Mary E.; Oler, Angie T.; Keller, Mark P.; Kendziorski, Christina; Broman, Karl W.; Yandell, Brian S.; Schadt, Eric E.; Attie, Alan D.

doi:10.1194/jlr.m025239

Cited by 10 publications

(13 citation statements)

References 63 publications

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“…For example, fatty acid oxidation and oxidative phosphorylation (OxPhos) proteins were increased with obesity (Figure 1C,G), while reactive oxygen species (ROS) detoxification enzymes were decreased (Figure S1C), consistent with known liver alterations (Buchner et al, 2011; Deng et al, 2010; Wang et al, 2012a). Phosphorylation changes were also prominent in a range of central mitochondrial (and non-mitochondrial) pathways (see mitomod.biochem.wisc.edu and Tables S1-5).…”

Section: Resultssupporting

confidence: 52%

A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis

et al. 2012

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Summary Mitochondria are dynamic organelles that play a central role in a diverse array of metabolic processes. Elucidating mitochondrial adaptations to changing metabolic demands and the pathogenic alterations that underlie metabolic disorders represent principal challenges in cell biology. Here, we performed multiplexed quantitative mass spectrometry-based proteomics to chart the remodeling of the mouse liver mitochondrial proteome and phosphoproteome during both acute and chronic physiological transformations in more than 50 mice. Our analyses reveal that reversible phosphorylation is widespread in mitochondria, and is a key mechanism for regulating ketogenesis during the onset of obesity and type 2 diabetes. Specifically, we have demonstrated that phosphorylation of a conserved serine on Hmgcs2 (S456) significantly enhances its catalytic activity in response to increased ketogenic demand. Collectively, our work describes the plasticity of this organelle at high resolution and provides a framework for investigating the roles of proteome restructuring and reversible phosphorylation in mitochondrial adaptation.

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Section: Resultssupporting

confidence: 52%

A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis

et al. 2012

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“…Also hepatitis (B/C) has been described to strongly alter hepatic lipid content and composition ( 15,16 ). Recently, the fatty acid elongase 6 (ELOVL6), which catalyzes the elongation of C16 to C18 fatty acids ( 17 ) and is a direct target of SREBF1 ( 18,19 ), has been shown to promote NASH in mice and humans and to be overexpressed in a murine NASH model ( 20,21 ). Interestingly, however, there is still a lack of understanding of the upstream signaling pathways that are responsible for SREBF1 activation and why elevated ELOVL6 increases total fatty acid production.…”

Section: Protein Isolation and Analysis By Western Blotmentioning

confidence: 99%

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Laggai

Kessler

Boettcher

et al. 2014

Journal of Lipid Research

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Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common liver disorder in Western countries with a prevalence of 20-30% of the adult population ( 1, 2 ). There is a strong correlation between the characteristics of the metabolic syndrome, such as obesity and diabetes mellitus, and NAFLD/nonalcoholic steatohepatitis (NASH) ( 3 ).The "two-hit" hypothesis represents a common model to describe the development and progression of fatty liver diseases. A simple steatosis can stand for the fi rst step in early liver pathogenesis ( 4, 5 ). The progression from simple steatosis to NASH requires a "second hit" mediated by reactive oxygen species and release of infl ammatory cytokines ( 6 ). This infl ammatory environment can result in hepatic cirrhosis and fi nally in hepatocellular carcinoma (HCC) ( 7 ).The development of hepatosteatosis can be induced by different mechanisms. The synthesis of lipids is regulated in a complex interplay induced by a set of lipogenic transcription factors, among which liver X receptor ␣ (LXR-␣ / NR1H3), sterol regulatory element binding transcription factor 1 (SREBF1/SREBP1), and carbohydrate responsive element binding protein (ChREBP/MLXIPL) represent the most important ones ( 8 ). In this context, the fact that MLXIPL controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression ( 9 ) illustrates the Abstract Liver-specifi c overexpression of the insulin-like growth factor 2 ( IGF2 ) mRNA binding protein p62/ IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 . Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These fi ndings underline the detrimental role of p62 in liver disease. -Laggai, S., S. M. Kessler, S.

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“…In cellular and animal models, hyper-activating mTORC1 (e.g. by deletion of TSC2) resulted in enhanced activation of SREBPs and their target genes(Duvel et al, 2010, Wang et al, 2012). Conversely, ablating mTORC1 activity via rapamycin treatment or liver-specific deletion of its essential subunit Raptor led to suppression of SREBP-dependent lipid biogenesis(Peterson et al, 2011, Porstmann et al, 2008).…”

Section: Lysosomal Mtorc1 Signaling In Control Of Lipid Biogenesis Anmentioning

confidence: 99%

Emerging Roles for the Lysosome in Lipid Metabolism

Thelen

Zoncu

2017

Trends in Cell Biology

207

156

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Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and non-vesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

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Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis

Cited by 10 publications

References 63 publications

A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis

A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Emerging Roles for the Lysosome in Lipid Metabolism

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