Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Hou, Wei; Syn, Wing–Kin

doi:10.3389/fcell.2018.00150

Cited by 75 publications

(72 citation statements)

References 99 publications

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“…We next explored the potential mechanism underlying costunolide suppression of HSC activation. Increasing evidence supports the notion that pharmacologically blocking aerobic glycolysis could be a novel strategy for reducing HSC activation and attenuating liver fibrosis [3]. For example, curcumin was found to inhibit the expression of several key molecules involved in glycolysis, leading to decreased viability and increased apoptosis in HSCs [18].…”

Section: Discussionmentioning

confidence: 93%

“…HSC activation is an energy-intensive process. Accumulating evidence suggests that activated HSCs use aerobic glycolysis as their major metabolic pathway in a phenomenon similar to the Warburg effect in cancer cells [3]. This metabolic switch is characterized by enhancement of glycolysis concomitant with repression of mitochondrial oxidative phosphorylation, even under normoxic conditions [4].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the highly proliferating HSCs can meet their energy and material requirements for cellular construction, despite the less efficient production of ATP in the glycolytic pathway. This suggests that inhibition of aerobic glycolysis could be a novel approach to reduce HSC activation and attenuate liver fibrosis [3].…”

Section: Introductionmentioning

confidence: 99%

“…2 The Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Kunshan 215300, China. 3 The Nanjing Integrative Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210014, China.…”

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confidence: 99%

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

et al. 2019

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Background Hepatic stellate cell (HSC) activation is a central event during hepatic fibrosis. Aerobic glycolysis is one of its metabolic hallmarks. Blocking glycolysis is a novel therapeutic option for liver fibrosis. This study investigated the effects of costunolide, a natural product demonstrated to have hepatoprotective effects, on HSC activation and glycolysis. Methods Primary HSCs were isolated from rats and cultured through 5 to 6 passages. Cell viability, activation markers, and glycolytic metabolism were examined in primary HSCs using various cellular and molecular approaches. Results At 30 μM, costunolide reduced the viability of HSCs and inhibited the expression of α-smooth muscle actin and collagen I, two key markers of HSC activation. It also decreased glucose uptake and consumption, and reduced the intracellular levels of lactate in HSCs. At 10 mM, the glycolysis inhibitor 2-DG had a similar impact to costunolide at 30 μM: it significantly downregulated the expression of HSC activation markers. The combination of the two compounds produced more remarkable effects. Furthermore, costunolide repressed the expression and activity of hexokinase 2 (HK2), a pivotal rate-limiting enzyme that regulates glycolysis. However, overexpression of HK2 via plasmid transfection significantly reversed the costunolide-mediated downregulation of activation markers in HSCs, indicating that suppression of HK2 was required for costunolide to inhibit glycolysis-associated HSC activation. Conclusions Our results show that costunolide can suppress HSC activation, and this is associated with inhibition of HK2, which blocks aerobic glycolysis. This suggests that costunolide is an antifibrotic candidate with potential for further development.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2019

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“…They are characterized by abundant lipid droplets composed of retinyl esters, triglycerides, cholesteryl esters, cholesterol, phospholipids, and free fatty acids (44). During hepatic injury, quiescent HSCs undergo profound phenotypic changes, including enhanced cell proliferation, loss of lipid droplets, and excessive production of the extracellular matrix in a process named activation (30). As such, they are considered key players in the development of hepatic fibrosis, regardless of etiology (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Ileal interposition surgery targets the hepatic TGF‐β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD‐T2DM rat model of diabetes

Hung,

Napoli,

Ross-Inta

et al. 2019

FASEB j.

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Ileal interposition (IT) is a surgical procedure that increases the delivery of incompletely digested nutrients and biliary and pancreatic secretions to the distal intestinal mucosa. Here, we investigated the metabolic impact of this intervention in 2‐mo‐old prediabetic University of California, Davis type 2 diabetes mellitus rats by assessing liver gene expression at 1.5 mo post‐IT surgery. Pathway analysis indicated decreased signaling via TGF‐β/Smad (a family of proteins named mothers against decapentaplegic homologs), peroxisome proliferator‐activated receptor (PPAR), and PI3K‐Akt‐AMPK–mechanistic target of rapamycin, likely targeting hepatic stellate cells because differentiation and activation of these cells is associated with decreased signaling via PPAR and TGF‐β/Smad. IT surgery up‐regulated the expression of genes involved in regulation of cholesterol and terpenoid syntheses and down‐regulated those involved in glycerophospholipid metabolism [including cardiolipin (CL)], lipogenesis, and gluconeogenesis. Consistent with the down‐regulation of the hepatic CL pathway, IT surgery produced a metabolic switch in liver, kidney cortex, and fat depots toward decreased mitochondrial fatty acid β‐oxidation, the process required to fuel high energy–demanding pathways (e.g., gluconeogenesis and glyceroneogenesis), whereas opposite effects were observed in skeletal and cardiac muscles. This study demonstrates for the first time the presence of metabolic pathways that complement the effects of IT surgery to maximize its benefits and potentially identify similarly effective, durable, and less invasive therapeutic options for metabolic disease, including inhibitors of TGF‐β signaling.—Hung, C., Napoli, E., Ross‐Inta, C., Graham, J., Flores‐Torres, A. L., Stanhope, K. L., Froment, P., Havel, P. J., Giulivi, C. Ileal interposition surgery targets the hepatic TGF‐β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD‐T2DM rat model of diabetes. FASEB J. 33, 11270–11283 (2019). http://www.fasebj.org

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Danshensu attenuated lipopolysaccharide‐induced LX‐2 and T6 cells activation through regulation of ferroptosis

Wang

et al. 2022

Food Science & Nutrition

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Liver fibrosis and cirrhosis are primarily caused by the activation of hepatic stellate cells (HSCs), regardless of their etiology. Collagen type I (collagen I) and connective tissue growth factor (CTGF) is produced more readily by activated HSCs. Consequently, identifying the molecular and cellular mechanisms responsible for HSCs activation is essential to better understand its mechanism of action and therapeutic potential. Cell death is caused by iron‐dependent lipid peroxidation during ferroptosis. Ferroptosis plays an important role in the survival of activated HSCs and could contribute to the development of innovative prevention and treatment strategies for liver fibrosis. Danshensu (Dan) is a pure molecule extracted from the Salvia miltiorrhiza herb that protects against liver damage. However, Dan's effect on attenuating HSCs activation by regulating ferroptosis remains unclear. The results of this study indicated that lipopolysaccharide (LPS)‐induced LX‐2 and T6 cells activation occurs through the upregulation of collagen I, CTGF, Gpx4, and SLC7A11. Interestingly, Dan attenuated LPS‐induced liver fibrosis in those cells by upregulating collagen I, CTGF, Gpx4, and SLC7A11 and by increasing lipid reactive oxygen species accumulation. Furthermore, the results also showed that the ferroptosis inhibitor liproxstatin attenuated the overproduction of lipid reactive oxygen species in LPS‐activated LX‐2 cells. We conclude that Dan attenuates LPS‐induced HSC activation during liver fibrosis by regulating ferroptosis in LX‐2 and T6 cells.

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Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Cited by 75 publications

References 99 publications

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

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

Ileal interposition surgery targets the hepatic TGF‐β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD‐T2DM rat model of diabetes

Danshensu attenuated lipopolysaccharide‐induced LX‐2 and T6 cells activation through regulation of ferroptosis

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