NEFA‐induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non‐alcoholic steatohepatitis

Abstract

The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non‐alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non‐esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF‐α and IL‐6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), mitofusin‐2 (Mfn‐2) and OXPHOS complexes (human: COI and COIII; cow: COI‐IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC‐1α and Mfn‐2 overexpression significantly decreased the NEFA‐induced ROS production and TNF‐α and IL‐6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS‐JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS‐JNK/p38MAPK pathway. PGC‐1α or Mfn‐2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH.

Expression patterns of hepatic genes involved in lipid metabolism in cows with subclinical or clinical ketosis

“…Increasing evidence demonstrated that ketotic cows suffered from NEB and decreased insulin sensitivity, both of which could initiate fat mobilization and increase the blood concentrations of fatty acids (Yuan et al, 2012;De Koster et al, 2015;Kawashima et al, 2016). High concentrations of fatty acids could impair the hepatic insulin signaling pathway and further decrease insulin sensitivity, which in turn disturbed the lipid metabolism (Barazzoni et al, 2012;Gao et al, 2018). Furthermore, the changes of many hormones involved in ketotic progression, such as fibroblast growth factor-21 (FGF-21) and bST (Schlegel et al, 2013;Gohary et al, 2014).…”

“…Highyielding dairy cows suffer from negative energy balance (NEB) and decreased insulin sensitivity during early lactation because of energy expenditure resulting from milk production and limited feed intake (Yuan et al, 2012;Kawashima et al, 2016). Negative energy balance initiates fat mobilization and a subsequent increase in the blood concentrations of fatty acids (Gross et al, 2013); high concentrations of fatty acids can impair the insulin signaling pathway, thereby decreasing the insulin sensitivity (Barazzoni et al, 2012;Gao et al, 2018). The decreased insulin sensitivity can further exacerbate fat mobilization and increase the blood concentrations of fatty acids in early-lactation cows, thereby initiating a vicious cycle (De Koster et al, 2015).…”

Effect of Caesalpinia bonduc Polyphenol Extract on Alloxan-Induced Diabetic Rats in Attenuating Hyperglycemia by Upregulating Insulin Secretion and Inhibiting JNK Signaling Pathway

“…MapK-8, also known as Jnk-1 (c-Jun N-terminal protein kinase 1), is critically involved in the generation of oxidative stress resulting in the induction of subsequent events of stress-induced apoptosis. Furthermore, activation of Jnk-1 gene leads towards inflammation of islets of Langerhans, pancreatic β cells dysfunction, and release of insufficient or defective insulin from β cells [72]. Under diabetic conditions, the JNK pathway is stimulated in many tissues, and this activation results in insulin resistance.…”

“…The pancreatic and duodenal homeobox 1 (Pdx-1) is an important gene involved in the development and functioning of β cells [72]. Similar to MafA, it is regarded as a key controller and regulator of glucose-stimulated insulin gene (Ins-1) transcription.…”

Edgeworthia gardneri (Wall.) Meisn. Water Extract Ameliorates Palmitate Induced Insulin Resistance by Regulating IRS1/GSK3β/FoxO1 Signaling Pathway in Human HepG2 Hepatocytes

“…The pathogenic mechanism underlying IR is complex and closely related to increased amounts of free fatty acids (FFAs) in plasma (Boden et al, 2001). In patients with T2DM, circulating FFAs directly enter into the liver; increased levels of hepatic FFAs can thus induce IR in the liver and activate some serine kinases, such as c-Jun-N-terminal kinase, p38, and ERK (Bi et al, 2013;Gao et al, 2018), leading to dephosphorylation of insulin receptor and its substrate 1/2 (IRS-1/2), thereby inhibiting Akt activity (Nakamura et al, 2009a). Subsequently, the downstream protein GSK3b was activated and the phosphorylation of FoxO1 was inhibited, resulting in the translocation of FoxO1 into the nucleus and triggers the hepatic IR (Cao et al, 2014).…”