Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.

Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through 'activation', and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the 'ductular reaction' as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.

Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis. Copyright © 2013 Elsevier Inc. All rights reserved.