Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

Abstract

ABSTRACT:Liver is the major organ that eliminates xenobiotics from the body, a process that is accomplished by a series of drug-processing genes (DPGs). These genes encode transporters on both basolateral and apical membranes of hepatocytes, as well as phase I and II enzymes. The current study compares the expression of hepatic DPGs in adult and aged mouse livers and explores the potential effects of energy restriction (ER) on these genes during aging. Of 79 quantified hepatic DPGs, 52 were expressed lower in 24-monthold aged mice than in 12-month-old adult mice. Furthermore, the mRNA expression of multiple xenobiotic-activated transcription factors also decreased with age. Six-month ER exerted less of an effect on the hepatic DPGs than did aging. ER increased the mRNAs of two and decreased the mRNAs of nine DPGs in adult mice. In aged mice, ER increased the mRNAs of 10 and decreased the mRNAs of 5 DPGs. The only mRNA that was increased by both ER and aging was Gstm3. ER increased the mRNAs of Cyp2b10, Ugt1a9, Gsta1, and Oatp1a4 only in adult mice and decreased the mRNAs of Aldh6a1, Pon3, Ugt1a1, Sult1a1, and Atp8b1 only in aged mice. In summary, the reduced mRNA expression of hepatic DPGs in aged mice indicates decreased drug-processing capability, whereas ER did not compensate for the global reduction of hepatic DPG expression in aged mice. The hepatic transcription factors are likely to mediate the changes in hepatic DPG expression during aging and ER.The geriatric population is rapidly increasing in the world. The proportion of persons aged 60 or older is projected to reach 22% of the global population in 2050, with 33% in more developed regions and 20% in less developed regions (United Nations Population Ageing and Development 2009, http://www.un.org/esa/population/ publications/ageing/ageing2009chart.pdf). Health care for this population presents a major medical and economic problem. The elderly population is more susceptible to various diseases, and they often take several drugs at the same time. Liver, the major organ for drug elimination from the body, exhibits decreased volume, diminished hepatobiliary functions, declined phase I drug metabolism capability, and increased or decreased expression of a variety of proteins in the elderly population (Schmucker, 2005).Liver metabolizes endogenous and exogenous compounds (nutrients and drugs), as well as maintains energy balance in the body. Numerous liver functions are accomplished by proteins encoded by a series of drug-processing genes (DPGs), which include basolateral uptake transporters, phase I and II enzymes, and apical and basolateral efflux transporters.Hepatocytes have transporters on both their basolateral and apical sides to remove xenobiotics from intestine-derived portal blood and to excrete them or their metabolites into bile or blood. Uptake solute carriers include organic anion-transporting polypeptides (Oatps), sodium/taurocholate-cotransporting polypeptide (Ntcp), organic cation transporters (Octs), organic anion transporters (Oats), and so...

Effect of Caloric Restriction and AMPK Activation on Hepatic Nuclear Receptor, Biotransformation Enzyme, and Transporter Expression in Lean and Obese Mice

“…CR decreased mRNA expression of Oatp1a1, Oapt1a4 and Oatp1b2 in lean mice, with protein expression following a similar trend in general . These observations, in part, agree with previously published data by (19). mRNA expression of efflux transporters of the ABC family did not follow a consistent pattern.…”

“…In lean mice, CR increased Cyp2b10 and Cyp4a14 mRNA expression, which is similar to previously published observations (19,32). Consistent with induction of Cyp2b10, Car mRNA expression was increased in lean mice, and induced in hepatocytes from lean mice treated with AICAR and NAD+, consistent with a previous report (33).…”

“…CR decreased Oatp1a1 and 1b2 mRNA, but not 1a4 mRNA expression in livers of lean mice (Fig. 4a) (19). Oatp1a1 and 1b2 expression remained low in livers OB mice even after CR, perhaps indicating importance for leptin-associated regulation.…”

“…Steatotic livers exhibit decreased AMPK pathway activity in rodents and increased activity can reverse fatty liver (16). CR alters activity and expression of various biotransformation enzymes, such as Sult2a1, Cyp2b10, Ugt1a1, Cyp4a14 in liver (17–19). However, to our knowledge, no studies have shown how CR actually affects drug transporter expression in livers of obese mice, which have hepatic steatosis and could better mimic the population most likely to undergo intervention.…”

Effect of nine diets on xenobiotic transporters in livers of mice

“…Altering the nutrients in diets of laboratory animals is a good method to investigate the effects of various diets, which are important in lifestyle diseases, especially when done at the same time to exclude complex genetic and husbandry variables. Previous studies have reported that mice fed a high-fat diet from 6 weeks of age had increased Mrp3/Abcc3 and 4 and decreased Mrp1/Abcc1 (More and Slitt, 2011); Western diet (high-fat/high-cholesterol diet) induced higher mRNA expression of hepatic Abcg5 and 8 in mice (Zhang et al , 2012); Atherogenic diet decreased Abcg8 transcripts (Cote et al , 2013); Diet-restriction for 6 months decreased Oatp1a1 and 1b2, while it increased Oatp1a4 in liver of mice (Zhang et al , 2010). However, no studies have comprehensively addressed how the expression of xenobiotic transporters is altered by numerous diets in the same experiment.…”