Background Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral ( R )-2-hydroxy FAs (( R )-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo . Findings FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with ( R )-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo . Moreover, ( R )-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that ( R )-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund Grants of NSF, NIH, and PAPD.

Supplementary key words adipose tissue • cyclooxygenase • eicosanoids • extracellular signal-regulated kinase • fatty acid • infl ammation • lipaseAdipose tissue is the major repository of excess energy stored in the form of triacylglycerol (TAG). During energy need, adipocyte lipolysis involving the hydrolysis of TAG releases FFAs for energy production by different tissues ( 1, 2 ). Adipose tissue also secretes various adipokines, which infl uence energy homeostasis and insulin sensitivity of distant tissues ( 3, 4 ). In addition to its important role in metabolic regulation, adipose tissue modulates the immune system by recruiting and activating lymphoid and myeloid cells when adipocyte fat storage is exaggerated as occurs in obesity ( 5 ). In obese individuals, there is a strong positive correlation between adipocyte size and the accumulation of proinfl ammatory adipose tissue macrophages (ATMs) ( 6, 7 ).However, ATM recruitment also occurs in mice after fasting or with calorie restriction ( 8 ) and in obese patients maintained on low-calorie diets during early weight loss ( 9 ), but under these conditions, it does not associate with infl ammation. The above fi ndings suggest that the mechanisms that operate in ATM recruitment in obesity or calorie restriction are not identical. Both fasting and pharmaceutically induced lipolysis increase macrophage content in adipose tissue, and lipolysis measures correlate with increased ATM content independent of adiposity ( 10 ). This suggests that lipid turnover and not lipid accumulation per se is Abstract Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic infl ammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinfl ammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specifi c lipid mediators with anti-infl ammatory properties are released from adipocytes undergoing lipolysis to induce macrophage migration. In the present study, we showed that conditioned medium (CM) from adipocytes treated with forskolin to stimulate lipolysis can induce migration of RAW 264.7 macrophages. In addition to FFAs, lipolytic stimulation increased release of prostaglandin E 2 (PGE 2 ) and prostaglandin D 2 (PGD 2 ), refl ecting cytosolic phospholipase A 2 ␣ activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-infl ammatory PGE 2 potently induced macrophage migration while different FFAs and PGD 2 had modest effects. The ability of CM to induce macrophage migration was abolished by treating adipocytes with the COX2 inhibitor sc236 or by treating macrophages with the prostaglandin E receptor 4 antagonist AH23848. In fasted mice, macrophage accumulation in adipose tissue coincided with increases of PGE 2 levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE 2 with infl ammation suppressive properties plays a signifi cant rol...

No abstract

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

No abstract