A dietary ketone ester mitigates histological outcomes of NAFLD and markers of fibrosis in high-fat diet fed mice

Nutritional ketosis as a therapeutic tool has extended to the treatment of metabolic diseases including - obesity, type 2 diabetes and nonalcoholic fatty liver disease. The purpose of this study was to determine whether dietary administration of the ketone ester (KE), R,S-1,3-butanediol diacetoacetate (BD-AcAc2), attenuates markers of hepatic stellate cell (HSC) activation and hepatic fibrosis in the context of high fat diet (HFD)-induced obesity. Six-week-old male C57BL/6J mice were placed on a 10-week ad libitum HFD (45% FAT, 32% CHO, 23% PRO). Mice were then randomized to 1 of 3 groups (n = 10 per group) for an additional 12 weeks: 1) control (CON), continuous HFD, 2) pair-fed (PF) to KE; and 3) KE (HFD+30% energy from BD-AcAc2, KE). KE feeding significantly reduced histological steatosis, inflammation and total NAFLD activity score vs CON, beyond improvements observed for calorie restriction alone (PF). Dietary KE supplementation also reduced the protein content and gene expression of pro-fibrotic markers (α-SMA, Col1a1, PDGF-β, MMP9) vs CON (p 0.05). These data highlight that the dietary ketone ester, BD-AcAc2, ameliorates histological NAFLD and inflammation and reduces pro-fibrotic and pro-inflammatory markers. Future studies to further explore potential mechanisms are warranted.