J Lipid Res. 2021 Sep 23. pii: S0022-2275(21)00105-X. [Epub ahead of print]
100123
Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline deficient (MCD) diet exhibited reduced hepatic triglycerides (TG), inflammation and fibrosis, associated with reduced oxidative stress and downstream activation of JNK and NFκB signaling pathways. However, when Mttpflox mice were fed a MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced but inflammation and fibrosis were increased after 10 days reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks MCD feeding, to 30 days led to sustained reductions in hepatic TG but neither inflammation nor fibrosis were decreased and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high fat/fructose/cholesterol diet for 10weeks, then switched to chow ± tamoxifen (HFFC→chow) or (HFFC→ Mttp-IKO chow), but again neither inflammation or fibrosis were affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50-90 fold reductions in hepatic TG.
Keywords: Intestine; antioxidant; apolipoproteinB; fibrosis; hepatic lipogenesis; intestinal permeability; lipid absorption; lipoproteins; microsomal triglyceride transfer protein; oxidative stress