Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression

Abstract

Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor-and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport.

Chimeric mouse model for MRI contrast agent evaluation

“…A final point to note is that only male mice were used in this study. While it is known that OATPs, and OATP1A1 in particular, have sex‐based differences in expression, they would not emerge in this study . However, it will be necessary to validate the sex‐based expression of chimeric OATPs in this model, and plan experiments accordingly.…”

Gene expression profiling after exposure to a chemical carcinogen, Pentabrominated Diphenyl Ether, at different life stages

“…For example, Abcc3 transcript, an efflux transporter, was upregulated after PBDE exposure in the liver, and upregulation of this membrane transcript is characteristic of preneoplastic and neoplastic hepatocellular lesions in humans and rodents ( Carrasco-Torres et al, 2016 ). Upregulation of membrane transporters is also characteristic of carcinogenesis processes in other organ systems ( Donepudi et al, 2016 ).…”

Systematic metabolomic studies identified adult adiposity biomarkers with acetylglycine associated with fat loss in vivo

“…The ATP-binding cassette (ABC) transporter pathway, a pivotal connector pathway, regulates the import/export of membrane proteins, such as thiamine, phthalate, L-glutamine, and glycine via different enzymes or reactions for the overall BF-related network (Rees et al, 2009). The pathway may delineate associations between genes and physiologic changes before, during, and after the onset of obesity in mice (Donepudi et al, 2016) and beneficial influences on obese women (Teixeira et al, 2020). However, we observed that phthalate in ABC transporters was negatively associated with A/G, A/W, and W%, in accordance with the findings from Hatch et al's study of BMI and waist circumference (Hatch et al, 2008).…”