IGF-1 Induces SREBP-1 Expression and Lipogenesis in SEB-1 Sebocytes via Activation of the Phosphoinositide 3-Kinase/Akt Pathway

The Jake Gittlen Cancer Research Foundation, Hershey, Pennsylvania, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 06/2008; 128(5):1286-93. DOI: 10.1038/sj.jid.5701155
Source: PubMed


Understanding the factors that regulate sebum production is important in identifying therapeutic targets for acne therapy. Insulin and IGF-1 stimulate sebaceous gland lipogenesis. IGF-1 increases expression of sterol response element-binding protein-1 (SREBP-1), a transcription factor that regulates numerous genes involved in lipid biosynthesis. SREBP-1 expression, in turn, stimulates lipogenesis in sebocytes. The goal of this study was to identify the intracellular signaling pathway(s) that transduces the lipogenic signal initiated by IGF-1. Sebocytes were treated with IGF-1 and assayed for activation of the phosphoinositide 3-kinase (PI3-K) pathway and of the three major arms of the mitogen-activated protein kinase (MAPK) pathway (MAPK/extracellular signal-regulated kinase (ERK), p38 MAPK, and stress-activated protein kinase/c-Jun-N terminal kinase). IGF-1 activated the MAPK/ERK and PI-3K pathways. Using specific inhibitors of each pathway, we found that the increase in expression of SREBP-1 induced by IGF-1 was blocked in the presence of the PI3-K inhibitor but not in the presence of the MAPK/ERK inhibitor. Furthermore, inhibition of the PI3-K pathway also blocked the IGF-1-induced transcription of SREBP target genes and sebocyte lipogenesis. These data indicate that IGF-1 transmits its lipogenic signal in sebocytes through activation of Akt. Specific targeted interruption of this pathway in the sebaceous gland could be a desirable approach to reducing sebum production and improving acne.

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Available from: Gary A Clawson, Oct 10, 2015
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    • "The major endocrine changes of puberty primarily depend on hepatic secretion of IGF-1, the principal mediator of somatic growth promoting sebaceous gland (SG) cell proliferation and lipogenesis 11–17. WD significantly increases insulin and IGF-1 serum levels and thus exaggerates already upregulated IIS of puberty 4,18. "
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    ABSTRACT: Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.
    Experimental Dermatology 05/2013; 22(5):311-5. DOI:10.1111/exd.12142 · 3.76 Impact Factor
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    • "Further exploration indicated that only co-presence of low TG plus low LDLC and neither of these two factors alone was associated with increased overall cancer risk in T2D (Yang et al. 2012a). Of note, insulin selectively activates SREBP1c, leading to upregulated synthesis of free fatty acids (Shimomura et al. 1999), while IGF1 activates SREBP1a, resulting in upregulated synthesis of both cholesterol and free fatty acids (Smith et al. 2008). As there is a feedback regulation loop from intracellular low cholesterol to IGF1 and SREBP1a to upregulate cholesterol synthesis (Brown & Goldstein 1997), we hypothesized that insulin insufficiency might lead to low Table 4 Additive interactions of HBsAg carrier status with enhancers and alleviators for HCC in type 2 diabetes. "
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    ABSTRACT: Chronic hepatitis B virus (HBV) infection promotes hepatocellular carcinoma (HCC) risk. In type 2 diabetes (T2D), use of insulin and statins was associated with reduced cancer risk while co-presence of low LDL cholesterol (LDLC <2.8 mmol/l) plus low triglyceride (TG; <1.7 mmol/l) increased cancer risk. There is experimental evidence showing that insulin insufficiency might promote HCC. In this study, we examined whether this lipid subphenotype and use of insulin or statins might modify the promoting effect of chronic HBV infection (indicated by the presence of hepatitis B surface antigen) on HCC. We analyzed data of 1319 T2D patients enrolled into the Hong Kong Diabetes Registry from December 1996 to January 2005 and followed up to 2005. Additive interaction was estimated using relative excess risk due to interaction and attributable proportion due to interaction. During 5782 person-years of follow-up, 1.74% (n=23) of patients developed HCC (incidence, 3.98; 95% confidence interval, 2.36-5.60/1000 person-years). HbA1c ≥7.0% and the lipid phenotype (LDLC <2.8 mmol/l plus TG <1.7 mmol/l) increased the hazard ratios (HRs) of chronic HBV infection for HCC from 3.74 to 74.96 and from 11.01 to 89.82 respectively with significant interactions. Use of insulin or statins decreased the HRs from 37.51 to 5.87 and from 64.94 to 16.99 respectively with significant interactions (all P values <0.05). These findings support our hypothesis that hyperglycemia and co-presence of low LDLC plus low TG might enhance, while insulin or statin usage might attenuate the promoting effect of chronic HBV infection on HCC in T2D.
    Endocrine Related Cancer 03/2013; 20(2):161-71. DOI:10.1530/ERC-12-0290 · 4.81 Impact Factor
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    • "After pretreatment with LY294002, the droplets were significantly abolished (Figure 2a), which was consistent with the results from flow cytometry analysis of Nile Red fluorescent dye intensity (Figure 2b). FAS, ACS, SCD, and HMGCR are all important enzymes with a role in lipid synthesis, whose gene transcription is regulated by SREBP-1 [12]. When DHT was introduced, the mRNA levels of FAS, ACS, SCD, and HMGCR were significantly increased. "
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    ABSTRACT: Background The purpose of this study was to investigate the effects and mechanisms of dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), and the synthesis and secretion of lipids, in HaCaT cells. HaCaT cells were treated with DHT and either the phosphoinositide 3-kinase inhibitor LY294002 or the extracellular-signal-regulated kinase (ERK) inhibitor PD98059. Real time-PCR, Western blot, Oil Red staining and flow cytometry were employed to examine the mRNA and protein expressions of SREBP-1, the gene transcription of lipid synthesis, and lipid secretion in HaCaT cells. Findings We found that DHT upregulated mRNA and protein expressions of SREBP-1. DHT also significantly upregulated the transcription of lipid synthesis-related genes and increased lipid secretion, which can be inhibited by the addition of LY294002. Conclusions Collectively, these results indicate that DHT induces SREBP-1 expression and lipogenesis in HaCaT cells via activation of the phosphoinositide 3-kinase/Akt Pathway.
    Lipids in Health and Disease 11/2012; 11(1):156. DOI:10.1186/1476-511X-11-156 · 2.22 Impact Factor
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