Aryl hydrocarbon receptor promotes lipid droplet biogenesis and metabolic shift in respiratory Club cells.

Club cells are critical in maintaining airway integrity via, in part, secretion of immunomodulatory Club cell 10 kd protein (CC10) and xenobiotic detoxification. Aryl hydrocarbon receptor (AhR) is important in xenobiotic metabolism, but its role in Club cell function is unclear. To this end, an AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ, 10 nM) was found to induce, in a ligand and AhR-dependent manner, endoplasmic reticulum stress, phospholipid remodeling, free fatty acid and triglyceride synthesis, leading to perilipin 2-dependent lipid droplet (LD) biogenesis in a Club cell-like cell line, NL20. The increase in LDs was due, in part, to the blockade of adipose triglyceride lipase to LDs, while perilipin 5 facilitated LDs-mitochondria connection, leading to the breakdown of LDs via mitochondrial ß-oxidation and acetyl-coA generation. In FICZ-treated cells, increased CC10 secretion and its intracellular association with LDs were noted. Administration of low (0.28 ng), medium (1.42 ng), and high (7.10 ng) doses of FICZ in C57BL/6 mice significantly enhanced lipopolysaccharide (LPS, 0.1 µg)-induced airway inflammation, mucin secretion, pro-inflammatory cytokines and CC10 in the bronchoalveolar lavage fluids, as compared to those seen in mice receiving LPS alone, suggesting the importance of AhR signaling in controlling the metabolic homeostasis and functions of Club cells.

AA genotype of PLIN1 13041A>G as an unfavourable predictive factor of malnutrition associated with fat mass loss in locally advanced head and neck cancer male patients treated with radiotherapy.

INTRODUCTION: Malnutrition is a frequently diagnosed condition in head and neck cancer (HNC) patients after radiation therapy (RTH). Malnutrition causes adipose tissue dysfunction associated with intensified lipolysis and disruption of the activity of mechanisms that protect adipose tissue against this process, which include the protective function of perilipin. MATERIAL AND METHODS: The purpose of this study was the evaluation of the predictive value of 13041A>G PLIN1 polymorphism in the development of malnutrition related to adipose tissue loss in a group of 80 patients with locally advanced HNC treated by means of radical radiation therapy. RESULTS: After the completion of RTH, men with AA genotype had significantly lower fat mass (FM compared to men with G haplotype; FM: 13.84 ± 6.36 kg and 19.06 ± 6.30 kg (p = 0.009). In consequence of RTH, the AA genotype carriers lost an average of 37.01% adipose tissue mass and patients with GA and GG genotypes lost 12.82 and 0.31% (p = 0.035), respectively. AA genotype was also associated with higher chance of ≥ 10%, ≥ 20% and ≥ 30% FM loss in the course of RTH (OR = 13.78; 5.78; 2.28). CONCLUSIONS: The evaluation of such molecular factors as SNP 13041A>G may have higher predictive value in the development of malnutrition associated with severe loss of fat mass than the subjective scales, e.g., SGA and NRS-2002. The presence of AA genotype on men with HNC before RTH may facilitate earlier nutritional intervention and supportive treatment aimed at limiting or preventing body mass and fat mass loss during the applied treatment.