Obesity risk and preference for high dietary fat intake are determined by FTO rs9939609 gene polymorphism in selected Indonesian adults.

BACKGROUND AND OBJECTIVES: Data suggest that genetic factors are associated with BMI. The fat mass and obesity- associated (FTO) gene modulates adipogenesis through alternative splicing and m6A demethylation. Individuals with FTO rs9939609 gene polymorphism have a preference for energy-dense foods. This study investigates the relationship between FTO rs9939609 and obesity and preference for dietary fat intake among selected Indonesian adults. METHODS AND STUDY DESIGN: A total of 40 non-obese and 40 obese participants aged 19-59 living in Jakarta were recruited. Body composition measurements included body weight, height, BMI, waist circumference, and body fat mass. Dietary intake was assessed using a semiquantitative food frequency questionnaire and food recall over 2 × 24-h periods. Genetic variation was determined using amplification-refractory mutation system polymerase chain reaction. RESULTS: The genotype distribution of the FTO gene (rs9939609) was at Hardy- Weinberg equilibrium (p=1) with minor allele frequency=0.19. Individuals with AT/AA genotypes had 3.72 times higher risk of obesity (p=0.009) and 5.98 times higher dietary fat intake (p=0.02) than those with TT genotype. Obese participants with the AT/AA genotypes had 1.40 times higher dietary fat intake than those with the TT genotype (p=0.016). CONCLUSIONS: These findings suggest that Indonesian adults with AT/AA genotypes of the FTO rs9939609 have higher obesity risks and preferences for high dietary fat intake than those with TT genotype.

Differentiation of pancreatic acinar cells to hepatocytes requires an intermediate cell type.

BACKGROUND & AIMS: The appearance of hepatic foci in pancreas has been well-documented in animal experiments and in patients with pancreatic cancer. We previously demonstrated that transdifferentiation of pancreatic exocrine cells to hepatocytes required members of the CCAAT enhancer binding protein family. Although the molecular basis of hepatic transdifferentiation is understood, the early cellular events remain to be defined. METHODS: Dexamethasone and oncostatin M were used to induce transdifferentiation of primary cultures of mouse acinar cells and exocrine cell lines into hepatocytes. Fluorescent-activated cell sorting was used to identify intermediate cell types and side-population characteristics. Cre-loxP-based lineage tracing was used to investigate whether acinar cells contribute directly to hepatocytes via intermediates that express adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2). RESULTS: Lineage tracing studies showed that hepatocytes were derived directly from pancreatic cells via ABCG2-expressing intermediates. Exposure of cells to insulin increased Akt phosphorylation, ABCG2 expression, and hepatic transdifferentiation. Inhibition of the phosphoinositide 3-kinase pathway, through addition of LY294002 or overexpression of a dominant-negative form of Akt, was sufficient to prevent transdifferentiation. When ABCG2-expressing cells were incubated with glucagon-like-peptide 1 or epidermal growth factor, the intermediate cells could differentiate into insulin-producing beta-like cells. CONCLUSIONS: The phosphoinositide 3-kinase pathway is important in the transdifferentiation of acinar cells to hepatocytes and those hepatocytes arise from acinar cells via ABCG2-expressing intermediates. Furthermore, ABCG2-expressing cells are multipotent and able to differentiate into hepatocytes and insulin-producing beta cells.

Porphyrin homeostasis maintained by ABCG2 regulates self-renewal of embryonic stem cells.

BACKGROUND: Under appropriate culture conditions, undifferentiated embryonic stem (ES) cells can undergo multiple self-renewal cycles without loss of pluripotency suggesting they must be equipped with specific defense mechanisms to ensure sufficient genetic stability during self-renewal expansion. The ATP binding cassette transporter ABCG2 is expressed in a wide variety of somatic and embryonic stem cells. However, whether it plays an important role in stem cell maintenance remains to be defined. METHODOLOGY/PRINCIPAL FINDINGS: Here we provide evidence to show that an increase in the level of ABCG2 was observed accompanied by ES colony expansion and then were followed by decreases in the level of protoporphyrin IX (PPIX) indicating that ABCG2 plays a role in maintaining porphyrin homoeostasis. RNA-interference mediated inhibition of ABCG2 as well as functional blockage of ABCG2 transporter with fumitremorgin C (FTC), a specific and potent inhibitor of ABCG2, not only elevated the cellular level of PPIX, but also arrest the cell cycle and reduced expression of the pluripotent gene Nanog. Overexpression of ABCG2 in ES cells was able to counteract the increase of endogenous PPIX induced by treatment with 5-Aminolevulinic acid suggesting ABCG2 played a direct role in removal of PPIX from ES cells. We also found that excess PPIX in ES cells led to elevated levels of reactive oxygen species which in turn triggered DNA damage signals as indicated by increased levels of gammaH2AX and phosphorylated p53. The increased level of p53 reduced Nanog expression because RNA- interference mediated inhibition of p53 was able to prevent the downregulation of Nanog induced by FTC treatment. CONCLUSIONS/SIGNIFICANCE: The present work demonstrated that ABCG2 protects ES cells from PPIX accumulation during colony expansion, and that p53 and gammaH2AX acts as a downstream checkpoint of ABCG2-dependent defense machinery in order to maintain the self-renewal of ES cells.