The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis

Abstract

Objective Obesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development. Methods A murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20 LKO ). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1– 13 C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways. Results Hepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20 LKO mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20 LKO mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20 LKO mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20 LKO mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice. Conclusions The hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients.

MicroRNA-379-5p regulates free cholesterol accumulation and relieves diet induced-liver damage in db/db mice via STAT1/HMGCS1 axis

“…In our work, we provide evidence to suggest that miR-379-5p negatively regulates STAT1 expression through transcriptional and post-transcriptional levels, showing the function of improving liver injury. HMGCS1 is one of the key enzymes in FC biosynthesis, and inhibiting its expression can reduce the FC synthesis pathway [ 39 ]. It has been reported that HMGCS1 is mainly regulated by SREBP2.…”

WY-14643 attenuates lipid deposition via activation of the PPARα/CPT1A axis by targeting Gly335 to inhibit cell proliferation and migration in ccRCC

“…NF-κB seems to be the culprit in the production of inflammation in the lipid-overloaded environment [ 8 , 56 ]. The direct involvement of NF-κB in lipid regulation has been further demonstrated [ 37 , 57 , 58 ]. Hence, in this study, NF-κB signaling was examined by western blotting and found to be suppressed after WY-14,643 was administered, which is consistent with previous results [ 39 ].…”

Mechanisms of Myocardial Damage Due to Hyperlipidemia: A Review of Recent Studies

“…The level of LDL in the serum increases and the level of oxLDL increases accordingly, which can activate NF-κB [ 30 ]. After the activation of NF-κB, on the one hand, it promotes the de-novo synthesis of cholesterol in the hepatocytes by inhibiting the AMPK pathway [ 31 ], and on the other hand, it inhibits the expression of PPARs. PPARs can reduce the level of TC7-hydroxylase (CYP7a1) in vivo [ 32 ].…”