No abstract

Background Non‐alcoholic fatty liver (NAFL) disease (NAFLD) is the most common chronic liver disease in the world. While most subjects have ‘inert’ NAFL, a subset will progress to non‐alcoholic steatohepatitis (NASH) and its life‐threatening complications. A substantial body of literature supports that a low muscle mass, low strength, and/or muscle fatty infiltration (myosteatosis) are associated with NAFLD severity. Here, we evaluated the muscle compartment in NASH preclinical models to decipher the kinetics of muscle alterations in relation with liver disease progression. Methods We developed and validated a micro‐computed tomography‐based methodology to prospectively study skeletal muscle mass and density in muscle and liver (i.e. reflecting fatty infiltration) in a high‐throughput and non‐invasive manner in three preclinical NAFLD/NASH rodent models: fat aussie (FOZ) mice fed a high‐fat diet (FOZ HF), wild‐type (WT) mice fed a high‐fat high‐fructose diet (WT HFF), and WT mice fed a high‐fat diet (WT HF). We compared them with WT mice fed a normal diet (WT ND) used as controls. Results ‐FOZ HF with fibrosing NASH had sarcopenia characterized by a reduced muscle strength when compared with WT HF and WT HFF with early NASH and WT ND controls (165.2 ± 5.2 g vs. 237.4 ± 11.7 g, 256 ± 5.7 g, and 242.9 ± 9.3 g, respectively, P 60; 0.001). Muscle mass or strength was not lower in FOZ HF, WT HF, and WT HFF with early NASH than in controls. Myosteatosis was present in FOZ HF with fibrosing NASH, but also in FOZ HF, WT HF, and WT HFF with early NASH (muscle density = 0.50 ± 0.02, 0.62 ± 0.02, 0.70 ± 0.05, and 0.75 ± 0.03, respectively, with P 60; 0.001 when compared with respective controls). Myosteatosis degree was strongly correlated with NAFLD activity score (r = −0.87, n = 67, P 60; 0.001). In multivariate analysis, the association between myosteatosis and NASH was independent from homeostatic model assessment of insulin resistance and visceral fat area (P 60; 0.05). Myosteatosis degree powerfully discriminated NASH from benign NAFL and normal liver (area under the receiver operating characteristic = 0.96, n = 67, P 60; 0.001). Conclusions Taken together, our data support that there is no sarcopenia in obese mice with early NASH. In contrast, the severity of myosteatosis reflects on hepatocellular damage and inflammation during early NASH development. This observation prompts us to exploit myosteatosis as a novel non‐invasive marker of NASH.

Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to “small for size syndrome” (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the “small for size syndrome” after extended hepatectomy or small liver transplantation.

After extended hepatectomy, hepatocyte proliferation proceeds sinusoidal endothelial cell (SEC) remodeling causing a transient perturbation of the lobular architecture with proliferating hepatocytes forming avascular, hypoxic, clusters. Hypoxia is, thus, considered at the origin of liver dysfunction in SFSS-hepatectomy. Recently, we showed that activation of hypoxia sensors in an upfront SFSShepatectomy surged an early angiogenic switch and preserved the sinusoidal architecture with a favorable impact on survival. Aim: to decipher the role hypoxia-induced angiogenesis in SFSS-setting hepatectomy. Methods: we developed a mouse model of SFSS-hepatectomy (PHx-80%) and used PHx-70% as controls. SFSShepatectomy mice were submitted to normoxia (inspired oxygen fraction-FiO 2 : 21%), local hypoxia (hepatic artery ligation (PHx-HAL)), and systemic hypoxia by placing the animals in hypoxic chambers (FiO 2 : 11%, PHx-HC). We assessed mortality, hepatocyte and liver SEC proliferation. Results: Compared to PHx-70%, PHx-80% showed high mortality rates (68% on postoperative day (POD) 7 (p=0,002)). Hepatocyte proliferation on POD 3 was higher in PHx-80% (p=0,03), while SEC proliferation did not differ, suggesting an amplified disorganization of the regenerating lobule in SFSS-hepatectomy. Compared to normoxic PHx-80%, PHx-HAL tended to have a favorable impact on survival (75% on POD3), while animals subjected to SFSS-hepatectomy and placed into hypoxic chambers showed improved survival (p=0,0007). Hepatocyte proliferation was similar between the hypoxic and normoxic SFSS-liver remnants. However, local and systemic hypoxia significantly triggered early angiogenesis. Conclusions: The current data suggest that hypoxia rescues survival from SFSS. By balancing angiogenesis with hepatocyte proliferation, hypoxia restores the lobular liver architecture allowing an efficient regeneration after major hepatectomy.

No abstract