Opaganib Protects Against High-Fat Diet-Induced Hypercholesterolemia and Liver Steatosis in Mice.

Introduction: Sphingolipid metabolism is involved in many diseases including cancer, pathologic inflammation, viral infection, neuropathology and metabolic disorders, including obesity and diabetes. Opaganib inhibits the key enzymes sphingosine kinase-2 and dihydroceramide desaturase and has anticancer, anti-inflammatory and antiviral activities in multiple experimental models. Opaganib has been studied in clinical trials with nearly 500 patients having cancer or severe Covid-19 and demonstrated an excellent safety profile. We recently showed that opaganib protects against high-fat diet (HFD)-induced obesity and glucose intolerance in mice. In the present studies, the effects of oral administration of opaganib for 12 weeks to already obese C57BL/6 mice fed HFD were further assessed. Methods: Male C57BL/6 mice were fed Control Diet or HFD for up to 31 weeks. The plasma pharmacokinetics of opaganib given either subcutaneously or orally at doses up to 150 mg/kg and the biodistribution of oral 100 mg/kg opaganib were determined. Additionally, 13-week HFD-fed mice were treated orally with 0 (vehicle) or 100 mg/kg/day, 5 days per week for an additional 12 weeks. Body weights were monitored for the 12-week treatment period, and blood chemistry was assessed at the end of the treatment period. Additionally, livers were harvested after 12 weeks of vehicle or opaganib treatment and were assessed for histological damage and inflammatory cytokine expression. Results: Pharmacokinetic analyses demonstrated that plasma opaganib exposure is dose-related with oral 100 mg/kg providing high drug exposure for at least 12 hours. After oral administration, opaganib distributed into all tissues examined (liver, small intestine, kidney and brain) and declined with elimination kinetics similar to those of plasma. Interestingly, the area under the plasma opaganib concentration curve for obese mice was substantially higher than in normal lean mice. As previously reported, opaganib treatment significantly suppressed weight gain in obese mice on HFD Treatment with opaganib also significantly attenuated HFD-induced elevations in plasma cholesterol, albumin and blood urea nitrogen levels, implying improved overall health of the obese mice. Furthermore, opaganib treatment blocked HFD-induced increases in liver weight and reduced microsteatosis and hypertrophy in the livers of mice sacrificed after the 12-week treatment period. Hepatic levels of the proinflammatory cytokines IL-6 and TNFα were also lowered with opaganib treatment but the decreases did not reach statistical significance. Conclusion: Overall, the present studies further support the ability of opaganib to suppress HFD-induced pathologies associated with obesity, hypercholesterolemia and liver steatosis in mice. Because opaganib has already demonstrated excellent safety in human clinical trials, this oral drug has potential for clinical testing for the prevention and treatment of obesity and related diseases, including hypercholesterolemia and liver steatosis.