Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells

Abstract

BackgroundContraction of hepatic stellate cells (HSCs) plays an important role in the pathogenesis of liver fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Here, we investigated how HSC contraction was affected by the natural compound oroxylin A, and elucidated the underlying mechanism.MethodsCell contraction and glycolysis were examined in cultured human HSCs and mouse liver fibrosis model upon oroxylin A intervention using diversified cellular and molecular assays, as well as genetic approaches.ResultsOroxylin A limited HSC contraction associated with inhibiting myosin light chain 2 phosphorylation. Oroxylin A blocked aerobic glycolysis in HSCs evidenced by reduction in glucose uptake and consumption and lactate production. Oroxylin A also decreased extracellular acidification rate and inhibited the expression and activity of glycolysis rate-limiting enzymes (hexose kinase 2, phosphofructokinase 1 and pyruvate kinas type M2) in HSCs. Then, we identified that oroxylin A blockade of aerobic glycolysis contributed to inhibition of HSC contraction. Furthermore, oroxylin A inhibited the expression and activity of lactate dehydrogenase-A (LDH-A) in HSCs, which was required for oroxylin A blockade of glycolysis and suppression of contraction. Oral administration of oroxylin A at 40 mg/kg reduced liver injury and fibrosis, and inhibited HSC glycolysis and contraction in mice with carbon tetrachloride-induced hepatic fibrosis. However, adenovirus-mediated overexpression of LDH-A significantly counteracted the oroxylin A’s effects in fibrotic mice.ConclusionsBlockade of aerobic glycolysis by oroxylin A via inhibition of LDH-A reduced HSC contraction and attenuated liver fibrosis, suggesting LDH-A as a promising target for intervention of hepatic fibrosis.Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0324-8) contains supplementary material, which is available to authorized users.

A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

“…Oroxylin A prevented from angiogenesis of LSECs in liver fibrosis via inhibition of the YAP/HIF-1 α signaling pathway [ 102 ]. Moreover, inhibition of glycolysis-dependent contraction via suppression of lactate dehydrogenase-A (LDH-A) and induction of apoptosis via endoplasmic reticulum (ER) stress in HSCs were involved in antihepatic fibrosis effects of oroxylin A [ 103 , 104 ]. Apart from these signaling pathways, oroxylin A also alleviated CCl 4 -induced liver fibrosis by activating autophagy signaling [ 105 ].…”

PFKFB3 Promotes Liver Fibrosis by Regulating Aerobic Glycolysis of Hepatic Stellate Cells

“…The natural product oroxylin destroys aerobic glycolysis through LDH-A, inhibits the contraction of HSCs, and reduces liver fibrosis (18). The well-known natural product curcumin can also inhibit aerobic glycolysis by HSCs, the mechanism of which is related to the activation of adenosine monophosphate-activated protein kinase (19).…”

Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2

“…Activation of AMPK was required for curcumin blockade of HSC glycolysis [19]. All three rate-limiting enzymes of glycolysis (HK2, PFK1 and PKM2) were inhibited by oroxylin A in HSCs, resulting in the restriction of HSC contraction [20].…”