NF-κB p65 regulates hepatic lipogenesis by promoting nuclear entry of ChREBP in response to a high carbohydrate diet

P Vineeth Daniel,Surbhi Dogra,Priya Rawat,Abhinav Choubey,Aiysha Siddiq Khan,Sangam Rajak,Mohan Kamthan,Prosenjit Mondal

doi:10.1016/j.jbc.2021.100714

P Vineeth Daniel, Surbhi Dogra + Show 6 more

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https://doi.org/10.1016/j.jbc.2021.100714

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Overconsumption of sucrose and other sugars has been associated with nonalcoholic fatty liver disease (NAFLD). Reports suggest hepatic de novo lipogenesis (DNL) as an important contributor to and regulator of carbohydrate-induced hepatic lipid accumulation in NAFLD. The mechanisms responsible for the increase in hepatic DNL due to overconsumption of carbohydrate diet are less than clear; however, literatures suggest high carbohydrate diet to activate the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP), which further transcribes genes involved in DNL. Here, we provide an evidence of an unknown link between nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) activation and increased DNL. Our data indicates high carbohydrate diet to enforce nuclear shuttling of hepatic NF-κB p65 and repress transcript levels of sorcin, a cytosolic interacting partner of ChREBP. Reduced sorcin levels, further prompted ChREBP nuclear translocation, leading to enhanced DNL and intrahepatic lipid accumulation both in vivo and in vitro. We further report that pharmacological inhibition of NF-κB abrogated high carbohydrate diet–mediated sorcin repression and thereby prevented ChREBP nuclear translocation and this, in turn, attenuated hepatic lipid accumulation both in in vitro and in vivo. Additionally, sorcin knockdown blunted the lipid-lowering ability of the NF-κB inhibitor in vitro. Together, these data suggest a heretofore unknown role for NF-κB in regulating ChREBP nuclear localization and activation, in response to high carbohydrate diet, for further explorations in lines of NAFLD therapeutics.

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Nonalcoholic fatty liver disease (NAFLD) is defined as a clinical state of excessive accumulation of lipids within hepatic tissue without any history of alcohol abuse
We found transcript levels of hepatic de novo lipogenesis (DNL) regulators (ACC, fatty acid synthase (FASN), carbohydrate response element-binding protein (ChREBP)) were increased in HSD exposed mice liver as compared with the NCD (Fig. 1D)
As we had recently identified sorcin as a novel regulator of ChREBP-linked DNL [20], we assessed for sorcin level in the HSD liver tissue

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Nonalcoholic fatty liver disease (NAFLD) is defined as a clinical state of excessive accumulation of lipids within hepatic tissue without any history of alcohol abuse. ChREBP binds to highly conserved carbohydrate response element regions across the promoters of ChREBP responsive target genes coding for key enzymes of DNL-like fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase [11]. A high carbohydrate diet is known to be an etiological parameter related to the development of metabolic diseases, ChREBP seems to be a hub protein that translates the carbohydrate-dependent signaling for glucose disposal as lipids [13, 14]. We observed high carbohydrate diet (30% sucrose for in vivo model and 30 mM glucose for in vitro model) to lower hepatic sorcin protein levels and thereby set cytosolic ChREBP free for nuclear entry and transcriptional activity. As dietary carbohydrate appears to be a universal causative agent of NAFLD progression, it seemed rationale to investigate the regulation of sorcin by high carbohydrate diet

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