P-glycoprotein Dysfunction Contributes to Hepatic Steatosis and Obesity in Mice

Abstract

Although the main role of P-glycoprotein (Pgp) is to extrude a broad range of xenochemicals and to protect the organism against xenotoxicity, it also transports a large range of endogenous lipids. Using mice lacking Pgp, we have investigated the possible involvement of Pgp in lipid homeostasis in vivo. In a long term study, we have followed the food intake, body status and lipid markers in plasma and liver of wild-type and mdr1ab-/- mice over 35 weeks. Pgp-deficient mice showed excess weight, hypertrophy of adipose mass, high insulin and glucose levels in plasma. Some of these metabolic disruptions appeared earlier in Pgp-deficient mice fed high-fat diet. Moreover, hepatosteatosis with increased expression of genes involved in liver detoxification and in de novo lipid synthesis occurred in Pgp-deficient mice. Overall, Pgp deficiency clearly induced obesity in FVB genetic background, which is known to be resistant to diet-induced obesity. These data reinforce the finding that Pgp gene could be a contributing factor and possibly a relevant marker for lipid disorder and obesity. Subsequent to Pgp deficiency, changes in body availabilities of lipids or any Pgp substrates may affect metabolic pathways that favour the occurrence of obesity. This is of special concern because people are often facing simultaneous exposition to many xenochemicals, which inhibits Pgp, and an excess in lipid dietary intake that may contribute to the high prevalence of obesity in our occidental societies.

Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex

“…(abcb1) knock-out mice with a high-fat diet induced obesity (Foucaud-Vignault et al, 2011). Likewise, in humans, a polymorphism of ABCB1 influencing transcription and function is associated with obesity (Ichihara et al, 2008).…”

Transintestinal Cholesterol Excretion Is an Active Metabolic Process Modulated by PCSK9 and Statin Involving ABCB1

“…Among the candidates, multidrug transporter ABCB1, which is located at the apical pole of enterocyte, can act as a cholesterol floppase. 23 We recently showed that older mice deficient for both isoforms of the apical cholesterol floppase ) spontaneously develop hepatic steatosis, obesity, diabetes mellitus, and increased HDL-C. 29 We performed our studies in 15-week-old male mice that presented with similar cholesterol levels ( Figure VIA in the online-only Data Supplement), before metabolic disturbances arise. We observed that ABCB1a/b −/− mice present with 26% less fecal cholesterol excretion (P<0.05; Figure 6A).…”

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

“…In addition to CYPs, pyrethroids may impact mammalian drug transporters, which contribute in a major way to xenobiotic detoxification [22] and are often coordinately regulated with drug metabolizing enzymes [23]. Indeed, activity of P-glycoprotein (P-gp), an ATP-binding cassette (ABC) efflux pump encoded by the multidrug resistance (MDR) 1 gene/ ABCB1 and handling a broad range of amphiphilic cationic drugs as well as various endogenous lipids [24, 25], has been shown to be inhibited by some pyrethroids [26, 27]. The ABC efflux pump breast cancer resistance protein (BCRP/ ABCG2 ) may also interfere with pyrethroids because its ATPase activity is blocked by the pyrethroids permethrin and cypermethrin [28].…”