TSC22D4 is a molecular output of hepatic wasting metabolism

Jones, Allan; Friedrich, Kilian; Rohm, Maria; Schäfer, Marcel; Algire, Carolyn; Kulozik, Philipp; Seibert, Oksana; Müller‐Decker, Karin; Sijmonsma, Tjeerd P.; Strzoda, Daniela; Sticht, Carsten; Gretz, Norbert; Dallinga‐Thie, Geesje M.; Leuchs, Barbara; Kögl, Manfred; Stremmel, Wolfgang; Díaz, Mauricio Berriel; Herzig, Stephan

doi:10.1002/emmm.201201869

Cited by 59 publications

(51 citation statements)

References 46 publications

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“…In line with these fi ndings, the literature describes that liver-specifi c knockout of FASN does not rescue the animals from the development of a fatty liver ( 64 ) and Jones et al ( 65 ) recently reported the development of a steatosis in TSC22D4 overexpressing mice despite decreased FASN mRNA levels. Most interestingly, animals overexpressing ELOVL6 also show increased liver triglycerides and at the same time reduced FASN expression ( 20 ).…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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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“…Last, hepatic steatosis has been documented in CAC patients (Teli et al 1995). At the molecular level, hepatic gene expression of the transcription factor TGFβ1-stimulated clone 22 D4 (TSC22D4) is increased in experimental cachexia and correlates with the degree of systemic wasting (Jones et al 2013). Gene expression levels of the nuclear receptor cofactor receptor-interacting protein 140 (RIP140) are also increased in CAC and may contribute to liver steatosis by preventing the release of TG stores (Berriel Diaz et al 2008).…”

Section: The Role Of the Liver In Cancer Cachexiamentioning

confidence: 99%

Mechanisms of metabolic dysfunction in cancer-associated cachexia

2016

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Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.

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“…Given the hypermetabolic and pro-inflammatory etiology of cachexia, disruption of liver functions could play a role in cachexia progression. Liver expression of TGFβ family transcription factor TSC22D4 correlates with body weight loss and VLDL hypo-secretion in the IL-6 dependent C26 cancer cachexia model [39]. Chronic IL-6 exposure during cachexia is also known to induce anemia and produce APPs, which provides further evidence of liver dysfunction [1, 28].…”

Section: The Liver As a Target Of Il-6mentioning

confidence: 99%

Role of interleukin-6 in cachexia

Narsale¹,

Carson²

2014

Current Opinion in Supportive &Amp; Palliative Care

173

148

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Purpose of review Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present recent breakthroughs in animal models and humans related to targeting IL-6 as a cancer cachexia therapy. Recent Findings IL-6 can target adipose, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient recovery. IL-6 trans-signaling through the soluble IL-6r has the potential to amplify IL-6 signaling in the cachectic patient. In skeletal muscle chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMPK and NF-κB activation. Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signaling can attenuate cachexia progression. Additionally, pharmaceuticals targeting IL-6 and associated signaling can relieve some cachectic symptoms in cancer patients. Research with cachectic mice has demonstrated that exercise and nutraceutical administration can interact with chronic IL-6 signaling during cachexia progression. Summary IL-6 remains a promising therapeutic strategy for attenuating cachexia progression with many types of cancer. However, improvement of this treatment will require a better understanding of the indirect and direct effects of IL-6 as well as its tissue specific actions in the cancer patient.

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TSC22D4 is a molecular output of hepatic wasting metabolism

Cited by 59 publications

References 46 publications

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

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

Mechanisms of metabolic dysfunction in cancer-associated cachexia

Role of interleukin-6 in cachexia

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