Dataset Information

High-fat diet feeding and palmitic acid increase CRC growth in ?2AR-dependent manner.

ABSTRACT: Epidemiology studies indicate that consumption of high-fat diet (HFD) is directly associated with the development of colorectal cancer (CRC). However, the exact component in HFD and the mechanism underlying its effect on CRC growth remained unclear. Our study shows that HFD feeding increases ?2AR expression in the xenograft tissues of CRC-bearing mouse model; the elevated ?2AR expression is reduced when HFD is replaced by control diet, which strongly suggests an association between HFD feeding and ?2AR expression in CRC. HFD feeding increases palmitic acid and stearic acid levels in CRC; however, only palmitic acid increases ?2AR expression, which is dependent upon Sp1. ?2AR plays the dominant role in promoting CRC cell proliferation among all the ?-AR subtypes. More importantly, knockout of ?2AR or knockdown of Sp1 abolishes the palmitic acid increased CRC cell proliferation, suggesting palmitic acid increases CRC cell proliferation in ?2AR-dependent manner. HFD or palmitic acid-rich diet (PAD) also fails to increase the tumor growth in xenograft mouse models bearing ?2AR-knockout CRC cells. ?2AR promotes CRC growth by increasing the phosphorylation of HSL at the residue S552. The phosphorylated and activated HSL (S552) changes the metabolic phenotype of CRC and increases energy production, which promotes CRC growth. Our study has revealed the unique tumorigenic properties of palmitic acid in promoting CRC growth, and have delineated the underlying mechanism of action. We are also the first to report the linkage between HFD feeding and ?-adrenergic signaling pathway in relation to CRC growth.

SUBMITTER: Fatima S

PROVIDER: S-EPMC6763436 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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High-fat diet feeding and palmitic acid increase CRC growth in β2AR-dependent manner.

Fatima Sarwat S Hu Xianjing X Huang Chunhua C Zhang Weixiong W Cai Jing J Huang Min M Gong Rui-Hong RH Chen Minting M Ho Alan H M AHM Su Tao T Wong Hoi Leong Xavier HLX Bian Zhaoxiang Z Kwan Hiu Yee HY

Cell death & disease 20190926 10

Epidemiology studies indicate that consumption of high-fat diet (HFD) is directly associated with the development of colorectal cancer (CRC). However, the exact component in HFD and the mechanism underlying its effect on CRC growth remained unclear. Our study shows that HFD feeding increases β2AR expression in the xenograft tissues of CRC-bearing mouse model; the elevated β2AR expression is reduced when HFD is replaced by control diet, which strongly suggests an association between HFD feeding a ...[more]

PMID: 31558710

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Project description:The gut microbiome is involved in metabolic disorders. Osteopontin (OPN), as a key cytokine, contributes to various inflammation-related diseases. The underlying role of OPN in the microbiome remains poorly understood. Here, we investigated whether OPN could modulate metabolic disorders by affecting gut microbiota. In our present study, we found that the expression of OPN was elevated in individuals with obesity compared to that observed in healthy controls. There was a positive correlation between plasma OPN levels and body mass index (BMI) in humans. Moreover, OPN significantly exacerbated lipid accumulation and metabolic disorders in high-fat diet (HFD)-fed mice. Importantly, OPN significantly aggravated HFD-induced gut dysbiosis with a key signature profile. Fecal microbiota transplantation also supported the role of OPN in HFD-induced metabolic disorders in a microbiota-dependent manner. Moreover, the microbiome shift of OPN-deficient mice would be compensated to resemble those of wild-type mice by feeding with either OPN-containing milk or recombinant OPN protein in vivo. Furthermore, metagenomic analysis showed that OPN induced a higher abundance of Dorea and a lower abundance of Lactobacillus, which were positively and negatively correlated with body weight, respectively. Indeed, the abundance of Dorea was significantly decreased after Lactobacillus administration, suggesting that OPN may regulate the intestinal abundance of Dorea by reducing the colonization of Lactobacillus. We further confirmed that OPN decreased the adhesion of Lactobacillus to intestinal epithelial cells through the Notch signaling pathway. This study suggested that OPN could exacerbate HFD-induced metabolic dysfunctions through the OPN-induced alteration of the gut microbiome. Therefore, OPN could be a potential therapeutic target for metabolic syndrome. IMPORTANCE Gut microbiota are involved in metabolic disorders. However, microbiome-based therapeutic interventions are not always effective, which might be due to interference of the host factors. Here, we identified a strong positive correlation between OPN levels and BMI in humans. Next, we confirmed that OPN could aggravate high-fat diet-induced metabolic disorders in mice. Importantly, we found that fecal microbiota transplantation from OPN-deficient mice significantly alleviated metabolic disorders in WT mice. OPN directly induces the remodeling of the gut microbiota both in vitro and in vivo. These findings indicate that OPN could contribute to metabolic disorders by inducing an alteration of gut microbiota. OPN regulated the relative abundance of Lactobacillus by decreasing the adhesion of Lactobacillus to intestinal epithelial cells through the Notch signaling pathway. These data identify OPN as a potential pharmaceutical target for weight control and for the treatment of metabolic disorders.

Dataset Information

High-fat diet feeding and palmitic acid increase CRC growth in ?2AR-dependent manner.

Publications

High-fat diet feeding and palmitic acid increase CRC growth in β2AR-dependent manner.

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