Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Arteel, Gavin Edward
Antipsychotics; Pharmacology; Olanzapine; Glutamine; Hepatology; Sulforaphane
Liver--Effect of drugs on; Liver--Diseases; Olanzapine
Olanzapine (OLZ) is an effective first-line treatment for schizophrenia and bipolar disorder. The benefits of OLZ are countermanded by side effects such as weight gain, glucose intolerance, dyslipidemia, and liver injury. These effects impact not only antipsychotic medication compliance, but also increase the health risks to patients. Most studies to date have focused on potential effects of OLZ on the central nervous system (e.g., hypothalamic regulation of satiety); however, peripheral changes in key metabolic organs such as the liver may also play a critical role. The obesity rates in the US are now at epidemic levels and obesity-induced liver disease (i.e., non-alcoholic fatty liver disease, or NAFLD) is on the rise. It is now understood that obesity is a significant risk factor for a myriad of drug-induced liver injuries. Given that the obesity incidence in the psychiatric population is even higher than in the US population as a whole, the effects of OLZ may exacerbate an underlying condition in these patients. The purpose of this work was to determine the mechanisms of OLZ-induced hepatic dysmetabolism, and to test the hypothesis that OLZ enhances obesity-induced hepatic injury. OLZ was administered in a mouse model for four weeks along with a high-fat diet (HFD) or low-fat control diet. OLZ alone increased body weight and caused mild glucose intolerance, without a commensurate increase in food consumption. OLZ alone also caused hepatic steatosis and injury. Interestingly, although OLZ increased hepatic triglyceride synthesis and storage, it did not increase the synthesis or abundance of hepatic free fatty acids. OLZ administration appeared to cause a pseudo-fasted state and dramatically depleted hepatic glycogen reserves. These effects of OLZ occurred in parallel to significant changes in hepatic metabolite profiles. The protein kinases AMPK and mTOR are generally differentially activated, and mediate opposing metabolic functions; however, OLZ administration simultaneously activated both AMPK and mTOR. When OLZ and HFD were combined, there was an even greater increase in weight gain and glucose intolerance. Liver damage from concurrent HFD and OLZ was worse than liver damage resulting from HFD or OLZ alone. Lastly, sulforaphane (SFN) was tested as a possible preventive against HFD- and OLZ-induced toxicity. Some mice receiving HFD and OLZ were also treated with SFN (90 mg/kg/d). SFN, a known inducer of the Nrf2 intrinsic antioxidant pathway, prevented weight gain and liver injury and rescued hepatic glycogen storage. Furthermore, SFN decreased the presence of 4-hydroxynonenal (4HNE) adducts in liver (>20-fold), indicating that SFN treatment substantially limits oxidative stress in this model. In summary, these data show that OLZ dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by HFD exposure. The outcomes of OLZ administration on hepatic metabolism may reflect, in part, the contradictory inputs of simultaneous AMPK and mTOR activation. These data indicate that the metabolic changes caused by OLZ may sensitize the liver to injury caused by HFD and that underlying obesity/liver disease may aggravate OLZ-induced side effects. The activation of intrinsic antioxidant defenses with SFN can partially prevent these effects of OLZ and may represent a useful strategy to protect against liver injury.
Schmidt, Robin H. 1984-, "Olanzapine-induced liver injury : direct metabolic effects, exacerbation by high-fat diet, and protection with sulforaphane." (2013). Electronic Theses and Dissertations. Paper 1272.