Chronic exposure to Pb²⁺ perturbs ChREBP transactivation and coerces hepatic dyslipidemia

Abstract

Dysregulated hepatic de novo lipogenesis contributes to the pathogenesis of nonalcoholic fatty liver disease in both humans and rodents. Clinical evidence suggests fatty liver to have a positive correlation with serum lead (Pb2+) levels. However, an exact mechanism of Pb2+‐induced fatty liver progression is still unknown. Here, we show that exposure to Pb2+ regulates ChREBP‐dependent hepatic lipogenesis. Presence of Pb2+ ions within the hepatocytes reduces transcript and protein levels of sorcin, a cytosolic adaptor partner of ChREBP. Adenovirus‐mediated overexpression of sorcin in Pb2+ exposed hepatocytes and an in vivo mouse model ameliorates liver steatosis and hepatotoxicity. Hereby, we present Pb2+ exposure to be a lethal disruptor of lipid metabolism in hepatocytes and highlight sorcin as a novel therapeutic target against Pb2+‐induced hepatic dyslipidemia.

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy

“…Indeed, environmental exposures such as heavy metals have been involved even though results are conflicting and possible mechanisms remain unclear [89]. Authors found that Pb2+ exposure could be a lethal disruptor of lipid metabolism in hepatocytes, and highlighted sorcin (a cytosolic adaptor partner of carbohydrate responsive element binding protein (ChREBP)-dependent hepatic lipogenesis) as a novel therapeutic target against Pb2+-induced hepatic dyslipidemia [90]. Hepatic de-novo lipogenesis (DNL) is a metabolic process proposed in the pathogenesis of T2DM, with multiple enzymes involved in this process [91].…”

Low-dose naltrexone rescues inflammation and insulin resistance associated with hyperinsulinemia

“…i.p of D-glucose. Insulin sensitivity was examined by the insulin tolerance test (ITT) in 6 hr fasted mice challenged with 0.5 units/kg ip insulin (39). The results were expressed by calculating the percentage of area under the glucose and basal insulin curve (AUC) using GraphPad Prism.…”

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

“…Following two PBS washes, cells were stained with Bodipy (2µM) for 30mins at 37 0 C. Cells were mounted using mounting media (Sigma) following three PBS washes and later visualized on a confocal microscope (A1+, Nikon) and representative images have been presented. Liver tissues were embedded in Tissue-Tek, frozen sections were then processed for ORO staining using a routine method 20 . Images were captured using Nikon Eclipse TS 100 confocal microscope.…”

“…Significant interaction sites of NF-κB were found on the promoter at 75 base pairs J o u r n a l P r e -p r o o f upstream to the transcription start site. Chromatin immunoprecipitation to assess occupancy of phosphorylated p65 along with co-repressor on sorcin promoter was performed as described previously 20 . Primers enriching the domain containing NF-κB consensus (-313bps to -22bps) were designed using the EPD tool.…”

“…Activation of ChREBP includes several posttranslational modifications like phosphorylation and acetylation as described in the cited articles ( 16 , 17 , 18 ). Cytoplasmic sequestration of ChREBP with adaptor proteins like 14-3-3β or sorcin stands out to be another promising axis of ChREBP activation ( 19 , 20 , 21 ).…”