Unsaturated Fatty Acids Increase the Expression of Hepassocin through a Signal Transducer and Activator of Transcription 3‐Dependent Pathway in HepG2 Cells

Abstract

Hepassocin (HPS) is a hepatokine that regulates hepatocyte proliferation. It is known that HPS plays an important role in the development of nonalcoholic fatty liver diseases (NAFLD). Fatty acids, such as oleic acid (OLA), exhibit the ability to activate the signal transducer and activator of transcription‐3 (STAT3), and the binding site of STAT3 is found in the promoter region of HPS. However, the regulation of HPS by fatty acids is still obscure. To clarify the regulation of HPS, we detected the expression of HPS by western blots. In addition, a hepatic steatosis cell culture model was established by treatment of different fatty acids, including linoleic acid (LNA), oleic acid, palmitic acid, and stearic acid. The intracellular lipid accumulation was confirmed by oil red O staining. Blocking of STAT3 activity was achieved by the pretreatment of the STAT3 inhibitor, stattic. We found that activation of STAT3 by interleukin‐6 (IL‐6) was mediated in the regulation of HPS expression. Treatment of unsaturated fatty acids significantly induced intracellular lipid accumulation in HepG2 cells. Moreover, the expressions of HPS were increased in unsaturated fatty acid‐treated HepG2 cells, as compared with saturated fatty acid‐treated groups. Also, the expression of HPS induced by OLA was blocked by the inhibition of STAT3 activity. Furthermore, we found that deletion of HPS by small interfering ribonucleic acid transfection decreased the protective effect of OLA on cell viability. Taken together, we provided evidence that STAT3 plays an important role in the regulation of OLA‐induced HPS expression and the increased HPS may further participate in the development of NAFLD. In addition, the increase of HPS might be involved in the protective effect of OLA on cell viability.

Circulating hepassocin level in patients with stable angina is associated with fatty liver and renal function

“…In addition, it is known that interleukin-6 (IL-6) increases hepassocin expression [27], indicating that elevated hepassocin might also be involved in obesity-induced IR. Furthermore, Cheng et al found that activation of signal transducer and activator of transcription-3 by IL-6 were mediated by hepassocin expression [28]. In the current study, it was revealed that the high hepassocin group had a higher waist-to-hip ratio compared with the low hepassocin group, and with increasing hepassocin tertiles, there were significant increases in hs-CRP concentrations as well as neutrophil and monocyte counts.…”

Implication of the hepatokine, fibrinogen-like protein 1 in liver diseases, metabolic disorders and cancer: The need to harness its full potential

“…Mechanistically, there are potential binding sites of STAT3 in the FGL1 gene promoter, and unsaturated fatty acid activates STAT3 to increase FGL1 expression. The blockade of STAT3 dose-dependently inhibited unsaturated fatty acid induced FGL1 expression, which accounts for the increased level of FGL1 under proinflammatory conditions [24]. In addition, FGL1 regulates NAFLD through an ERK1/2-dependent pathway [22].…”

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

“…HPS expression in BAT and liver was increased following partial hepatectomy in mice [110] and by IL-6 in vitro [107], suggesting a cross talk between the injured liver and adipose tissue [110]. Oleic acid increased HPS expression via activation of Signal transducer and activator of transcription 3 (STAT3) signaling and induced IR in HepG2 cells [111], while palmitic acid induction of HPS occurred through p38-modulated CCAAT/enhancer binding protein binding to the HPS promoter in mice [112]. HPS administration protected against liver injury and improved the survival of lethal hepatitis in rats [113].…”