Abstract
Activation of hepatic stellate cells (HSCs) is an integral component of the wound‐healing process in liver injury/inflammation. However, uncontrolled activation of HSCs leads to constant secretion of collagen‐rich extracellular matrix (ECM) proteins, resulting in liver fibrosis. The enhanced ECM synthesis/secretion demands an uninterrupted supply of intracellular energy; however, there is a paucity of data on the bioenergetics, particularly the mitochondrial (mito) metabolism of fibrogenic HSCs. Here, using human and rat HSCs in vitro, we show that the mito‐respiration, mito‐membrane potential (Δψm) and cellular ‘bioenergetic signature’ distinguish fibrogenic HSCs from normal, less‐active HSCs. Ex vivo, HSCs from mouse and rat models of liver fibrosis further confirmed the altered ‘bioenergetic signature’ of fibrogenic HSCs. Importantly, the distinctive elevation in mito‐Δψm sensitized fibrogenic HSCs for selective inhibition by mitotropic doxorubicin while normal, less‐active HSCs and healthy human primary hepatocytes remained minimally affected if not, unaffected. Thus, the increased mito‐Δψm may provide an opportunity to selectively target fibrogenic HSCs in liver fibrosis.
Highlights
Liver cirrhosis represents a worldwide health problem, and epidemiology data indicate that 70–80% of cirrhotic patients will develop the primary liver cancer, hepatocellular carcinoma [1, 2]
Alteration in the metabolic phenotype, the mitochondrial metabolism has recently been reported in cirrhosis, yet data on fibrogenic hepatic stellate cells (HSCs), the critical determinant of fibrosis, remain unknown [12, 13]
Results from the analysis of mitochondrial respiration showed a striking elevation in the oxygen consumption rate (OCR) of fibrogenic HSCs compared to the normal, less-active counterpart as demonstrated from human HSC, LX-2 and rat HSCs (Fig. 2A and C)
Summary
Liver cirrhosis represents a worldwide health problem, and epidemiology data indicate that 70–80% of cirrhotic patients will develop the primary liver cancer, hepatocellular carcinoma [1, 2]. Chronic inflammation and/or injury to the liver parenchyma results in liver fibrosis that advances to cirrhosis [3]. The excessive accumulation of ECM contributes to the transformation of normal liver parenchyma into a fibrogenic or fibrotic phenotype. The efficiency of energy producing pathways (e.g. glucose metabolism) is critical for the progression of fibrosis. Among the energy-producing pathways, mitochondrial (mito) metabolism (oxidative phosphorylation [OxPhos]) and glycolysis (conversion of glucose into pyruvate followed by lactate production) have been known to be altered in early and later stages of cirrhosis [13]. The distinctive mito-Dwm enabled selective targeting of fibrogenic HSCs by TPP-doxorubicin while normal HSCs and human primary hepatocytes remained minimally affected if not, unaffected. The elevated mito-Dwm may provide a window of opportunity to selectively target fibrogenic HSCs in liver fibrosis
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