Metabolomic characteristics of cholesterol-induced non-obese nonalcoholic fatty liver disease in mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) in non-obese patients remains a clinical condition with unclear etiology and pathogenesis. Using a metabolomics approach in a mouse model that recapitulates almost all the characteristic features of non-obese NAFLD, we aimed to advance mechanistic understanding of this disorder. Mice fed high fat, high cholesterol, cholate (HFHCC) diet for three weeks consistently developed hepatic pathology similar to NAFLD and nonalcoholic steatohepatitis (NASH) without changes to body weight or fat pad weights. Gas- and liquid chromatography/mass spectrometry-based profiling of lipidomic and primary metabolism changes in the liver and plasma revealed that systemic mechanisms leading to steatosis and hepatitis in this non-obese NAFLD model were driven by a combination of effects directed by elevated free cholesterol, cholesterol esters and cholic acid, and associated changes to metabolism of sphingomyelins and phosphatidylcholines. These results demonstrate that mechanisms underlying cholesterol-induced non-obese NAFLD are distinct from NAFLD occurring as a consequence of metabolic syndrome. In addition, this investigation provides one of the first metabolite reference profiles for interpreting effects of dietary and hepatic cholesterol in human non-obese NAFLD/NASH patients.

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

“…Mice were fed either a cholesterol-rich (ChR) or a high-sucrose diet for 16 weeks. Mice fed the ChR diet remained lean despite the development of NAFLD, which is consistent with other studies, (23,24) whereas those fed the high-sucrose diet demonstrated significant weight gain. Histology images are shown in Fig.…”

“…Lean NAFLD had an increased abundance of members belonging to the Clostridium genus as well as Ruminococcaceae, which are involved in the formation of BAs . Consistently, in an experimental model that involved feeding mice a ChR diet, we recapitulated several features of the phenotype, including lean body weight, steatohepatitis, and less insulin resistance, compared with mice receiving a high‐sucrose diet, with similar changes in BA profiles with higher total BAs and fgf15 levels and similar trends observed in gut microbiota. Thus, we surmise that patients with lean NAFLD have an obesity‐resistant phenotype in part mediated by greater levels of BAs and FGF19 and microbiota changes.…”

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis paniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet

“…However, plasma triglyceride concentration was lower (p < 0.05) than that of the control group. This observation has also been observed in previous studies [6,8,34], as very low density lipoprotein (VLDL) secretion may have been impaired after feeding with the HFHC diet [34]. Mice fed a HFHC diet with 0.05% or 0.1% deAND supplementation had a reduced (p < 0.05) total plasma cholesterol concentration with no change in plasma triglyceride concentration when compared with the animals fed an HFHC diet.…”

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…Citrate, G-1-P, and saccharic acid were all downregulated in these livers. Subtle differences were reported for plasma of HFDCC-fed mice, including elevated total cholesterol, CE(16:1), (18:1), (18:2), (18:3), (20:1), (20:3), (20:4), (22:5), cholic acid, deoxycholic acid, CERs, SMs, and PEs, while FFAs, glycerol, TGs, and LPEs were all diminished in pathological livers [225]. Xanthosine, the ribonucleoside of xanthine, could be a potential biomarker when evaluated in patients.…”