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

Abstract

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.

Elevated expression of the IGF2 mRNA binding protein 2 (IGF2BP2/IMP2) is linked to short survival and metastasis in esophageal adenocarcinoma

“…This is in line with other studies which reported that IMP2 is involved in obesity and liver steatosis [18–20]. In steatohepatitis IMP2 overexpression led to the accumulation of free cholesterol and the activation of a fatty acid elongase [21, 22]. The observed correlation of IMP2 and signaling pathways such as MAPK and Jak-STAT seems reasonable since IMP2 expression results in increased levels of IGF2 [20], which can activate both of these pathways.…”

Methylation of imprintedIGF2regions is associated with total, visceral, and hepatic adiposity in postmenopausal women

“…We also observed a significant direct positive association of methylation levels in the IGF2 DMR2a with percent liver fat and liver fat. Other studies have shown that IGF2 may play an important role in abnormal liver conditions [54][55][56]. For example, IGF2 was shown to be involved in lipid metabolism in liver diseases [54], and to be highly expressed in non-alcoholic steatohepatitis [55] and hepatocellular carcinoma [56].…”

miR‐1275: A single microRNA that targets the three IGF2‐mRNA‐binding proteins hindering tumor growth in hepatocellular carcinoma

“…They are re‐expressed in various tumors, including HCC, where their high expression is correlated with tumor invasion, early recurrence, and poor prognosis [11–15]. Moreover, IGF2BPs may play a detrimental role in malignant transformation of the liver as they have been reported to induce lipogenesis and steatohepatitis [16] and promote non‐alcoholic fatty liver disease, which are well‐recognized risk factors for HCC [17]. In addition, the IGF2BPs have been linked to cancer at the molecular level in several in vivo and in vitro studies, where they were reported to control the post‐transcriptional fate of numerous oncogenic transcripts such as IGF‐2 , MYC , KRAS , and MKI67 [12,14,18–20].…”

“…They are re-expressed in various tumors, including HCC, where their high expression is correlated with tumor invasion, early recurrence, and poor prognosis [11][12][13][14][15]. Moreover, IGF2BPs may play a detrimental role in malignant transformation of the liver as they have been reported to induce lipogenesis and steatohepatitis [16] and promote non-alcoholic fatty liver disease, which are well-recognized risk factors for HCC [17]. In addition, the IGF2BPs have been linked to cancer at the http://dx.doi.org/10.1016/j.febslet.2015.06.038 0014-5793/Ó 2015 Federation of European Biochemical Societies.…”