br Acknowledgements br Introduction Obesity is

Acknowledgements
Introduction Obesity is a growing pandemic, which becomes a global public health problem. The evidence has been readily available and mounting, demonstrating that obesity increases incidences of chronic comorbidities, such as non-alcoholic fatty liver diseases, diabetes, cardiovascular diseases and cancer [1], [2]. In particular, obesity-associated comorbidities require drug treatments [3]. In the clinic, pharmacokinetics and pharmacodynamics of many therapeutic drugs are changed in an obesity individual [4], but the mechanism is still not completely understood. Drug metabolism and pharmacokinetics (DMPK) result in the breakdown and safe elimination of a parent drug through a detoxification pathway. The process predominantly occurs in the liver through Sulfo-NHS-Biotin responsible for the modification of functional groups (phase I reactions) and the conjugation of endogenous substituent to drugs to make them even more hydrophilic (phase II conjugation) [5]. For example, cytochrome P450(CYP) enzymes, the main phase I enzymes, metabolize almost 75% drugs on the market, and play a primary role in the biotransformation of endogenous molecules and xenobiotics [6]. The main CYP isoforms in humans include CYP3A4/5, CYP2C9/19, CYP2D6, CYP1A1/2 and CYP2E1, participating in nearly 95% of CYP-mediated reactions [7]. Phase II metabolic processes include glucuronide-, N-acetyl-, methyl-, glutathione-, and sulfate- conjugation of substrates, which further increase hydrophilicity, enabling metabolites to be exported into the sinusoidal circulation for renal clearance, or into bile. Phase II enzymes include uridine diphosphate glucuronosyltransferase (UGT), sulfotransferases (SULT), glutathione S-transferase (GST) and Nacetyltransferase 2 (NAT2). UGT enzymes as the most important phase II enzymes catalyze the conjugation of various endogenous substances and exogenous compounds [8]. In addition, hepatic transporter proteins play a key role in both the influx and efflux of endogenous and xenobiotics compounds into and out of the cell. Basolateral influx transporters participate in the hepatic uptake of xenobiotics and conjugated bile acids from the liver sinusoids. This transporter super family includes sodium taurocholate co‐transporting polypeptides (NTCP/SLC10A1), members of the organic anion transporter (OAT) and organic anion‐transporting polypeptide (OATP/SLCO) families. Meanwhile, transporters located at the apical membrane are involved in the efflux of both drug metabolites and bile constituents into the bile canaliculus. The ATP‐binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known asP-glycoproteinor P-gp, ABCB1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and breast cancer resistance protein (BCRP, ABCG2) are the most representative efflux transporters with broad substrate specificity that has been associated with cellular resistance to many drugs [9], [10]. Differences in CYP activity, accompanying significant interindividual discrepancy in DMPK, have been found in patients with various kinds of disease. In particular, drug pharmacokinetics is altered in obese, nonalcoholic fatty liver disease (NAFLD) and diabetic patients [11]. Previous studies have reported that CYP3A expression is decreased in human NAFLD in addition to mouse and in vitro cell models of the disease [12]. The mRNA expression of CYP3A11 and CYP3A25 were reduced in both the liver and kidneys of diet-induced obesity mice, which correlated with a significant decline in midazolam metabolism [13]. The plasma exposure of atorvastatin was significantly decreased in diabetic rats induced by high-fat diet and streptozotocin because of the up-regulated activities and expressions of both hepatic CYP3A and OATP2 [14].
Materials and methods
Results
Discussion Changes in physiological and pathophysiological conditions, including obesity, fatty liver and diabetes, often alter the expression of important enzymes and transporters in the liver, but the mechanisms remain unclear. In this study, we assessed the effects of diet-induced obesity and its associated fatty liver on phase I and II enzymes, transporters and nuclear receptors in male rats. After 12-week diet treatments, the HFD rats gained more body, adipose tissue and liver weight than those from LFD group rats, suggesting that the model of diet-induced obesity was successfully established. In the liver of obese rats, the expression and activity of phase I enzymes (CYP1A2, CYP2B1, CYP2C11, CYP3A1, CYP4A1 and FMO1), and phase II enzymes (UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, NAT1 and GSTT1) were significantly decreased compared to these of lean control rats. The mRNA levels of transporter Slco1a2, Slco1b2, Slc22a5, Abcc2, Abcc3, Abcb1a, and Abcg2 was also decreased, whereas Abcb1b was dramatically increased in obese rats. These results showed that diet-induced obesity disturbed hepatic drug metabolizing enzymes and transporters.