Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology

Abstract

Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and temporal components. Spatial distribution of metabolic function in hepatocytes of different lobular zones is necessary to perform complex sequential multistep metabolic processes and to assign metabolic tasks to the right environment. Moreover, temporal control of metabolic processes is critical to align required metabolic processes to the feeding and fasting cycles. Disruption of this complex spatiotemporal hepatic organization impairs key metabolic processes with both local and systemic consequences. Many metabolic diseases, such as nonalcoholic steatohepatitis and diabetes, are associated with impaired metabolic liver zonation. Recent technological advances shed new light on the spatiotemporal gene expression networks controlling liver function and how their deregulation may be involved in a large variety of diseases. We summarize the current knowledge about spatiotemporal metabolic liver zonation and consequences on liver pathobiology.

LiverZap: A chemoptogenetic tool for global and locally restricted hepatocyte ablation to study cellular behaviours in liver regeneration

“…The zebrafish NTR-MTZ liver regeneration models elicit organ-wide tissue damage, while locally restricted hepatocyte ablation cannot be recapitulated (Curado et al ., 2008), which is a limitation considering that clinically relevant hepatic injury is often regionally restricted (Martini et al ., 2023). We therefore tested whether restricted NIR illumination could activate LiverZap locally instead of globally.…”

“…Under physiological conditions, liver damage is often locally restricted, for example non-alcoholic fatty liver diseases originate pericentrally in human, while autoimmune hepatitis starts periportally (Martini et al ., 2023). Regenerative processes consequently take place at the junction of healthy and diseased tissue.…”

“…Under physiological conditions, liver damage is often locally restricted, for example nonalcoholic fatty liver diseases originate pericentrally in human, while autoimmune hepatitis starts periportally (Martini et al, 2023) global hepatocyte death as previously shown (Choi et al, 2014;He et al, 2014;Manco et al, 2019;Raven et al, 2017;So et al, 2020). Instead, it suggests that the ratio of lost hepatocytes to BECs in a defined area may be sufficient to elicit this repair program.…”

“…Furthermore, regeneration initiates concomitant with ongoing cell ablation in these models, which hinders the distinction of the two processes. Finally, investigating the interface between regenerating and healthy tissue, relevant to human disease in which tissue damage is heterogeneous across the liver(Martini et al, 2023) is not possible using global hepatocyte ablation systems. Optogenetic approaches (Varady and Distel, 2020) provide both precise spatial and temporal control of tissue manipulation.…”

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

“…Therefore, learning had to be transferred from each perfusion to the next. To promote defatting without compromising organ viability, several protocol adaptations proved to be favorable during our assessments (Table 1): (i) no glucose supplementation to the nutrition to minimize lipogenesis; 29,30 (ii) consequently, a feedback loop had to be integrated by combining automated insulin (hyperglycemia) and glucagon (hypoglycemia) infusion coupled to a real-time glucose sensor as to maintain normoglycemia; (iii) major nutrition inflow was limited to 3 circadian peaks corresponding to daily meals, resulting in improved preservation of lobular zonation (eg, glutamine synthetase (GS), Supplemental Figure 3, Supplemental Digital Content 1, http://links.lww.com/SLA/E776), an indirect measure for metabolic functionality; 31 (iv) daily supplementation with L-carnitine (transport of fatty acids into mitochondria) and fenofibrate (activation of PPARα, key transcription factor promoting β-oxidation) eventually was integrated to stimulate lipid oxidation. The outcomes of the above adaptations are described below.…”