The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2–mechanistic target of rapamycin–cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.

Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.

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This study elucidates how Mg content affects the microstructure and mechanical properties of Al-14.5Si-4.5Cu alloy by adding 0.45 and 0.90 wt pct Mg. Primary silicon, eutectic silicon, acicular b-Al 5 FeSi, Al 2 Cu, and Al 5 Cu 2 Mg 8 Si 6 phases were observed under the as-cast condition in low-Mg alloy. In high-Mg alloy, a large proportion of the acicular b-Al 5 FeSi phase was converted to Chinese script Al 8 Mg 3 FeSi 6 phase. Neither the acicular b-Al 5 FeSi phase nor the Chinese script Al 8 Mg 3 FeSi 6 phase dissolved in the Al matrix during solution heat treatment. Tensile testing indicates that T6-treated high-Mg alloy containing the Chinese script Al 8 Mg 3 FeSi 6 phase is better than the T6-treated low-Mg alloy that contains the acicular b-Al 5 FeSi phase. The morphologies of Chinese script Al 8 Mg 3 FeSi 6 and acicular b-Al 5 FeSi phases affect the tensile properties of Mg-containing Al-14.5Si-4.5Cu alloys. Additionally, high-Mg alloy contains a higher concentration of Mg solute atoms in the Al matrix than low-Mg alloy, and so the former contains more k¢ precipitates (Al 5 Cu 2 Mg 8 Si 6 ) after T6-tempering treatment. The large amount of k¢ that precipitates in T6-treated high-Mg alloy may also enhance its tensile strength. The ultimate tensile strength (UTS) and elongation of the high-Mg alloy are superior to those of the low-Mg alloy.

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