Glori Das

Introduction: An estimated 25% of the global population suffers from Non-Alcoholic Fatty Liver Disease (NAFLD)¹. NAFLD is a progressive condition characterized by hepatocyte lipid accumulation (HLA) and fibrosis in its more advanced stages. Multiple pathways controlled by noradrenergic (NAergic) signaling have been implicated in NAFLD pathogenesis^2,3,4. The goal was to investigate hepatic nerve injury caused by NAergic hyperexcitability as a unifying explanation for the multiple mechanisms contributing to NAFLD. Methods: In one study, researchers compared HLA, nerve fiber densities (NFDs), and portal vasculature in wild-type (WT), WT + Western diet-fed (WD), and SNAP-25^-/- obese + WD mice⁵. These researchers also compared HLA and NFDs in control and Vav3^-/- mouse models of sympathetic hyperactivity. Oil-Red-O staining of mouse liver sections was used to visualize HLA. For NFD quantification and 3D visualization, iDISCO+ volume immunostaining was combined with light-sheet fluorescence microscopy. In a different study, researchers co-cultured celiac ganglia neurons with Kupffer macrophages (KMs) in vitro from WT+ WD mice to investigate the inflammatory pathway responsible for NAergic denervation⁶. NE’s role in said inflammatory pathway and insulin responsiveness was quantified using qRT-PCR and Western blot analysis, respectively. Results: WT + WD livers were found to be effective models of steatosis, while SNAP-25^-/- + WD livers were effective models of steatohepatitis⁵. Significant denervation was found in the steatohepatitis model. Interestingly, axon sprouting and nerve growth factor upregulation were found in the steatosis but not in the steatohepatitis model. Both models showed axon ballooning and fiber disorganization that correlated with worsening NAFLD. Portal stenosis correlated with worsening portal denervation in the steatohepatitis model, indicating a connection between NAFLD and portal hypertension. Studies of Vav3^-/- mice confirmed that sympathetic hyperactivity is responsible for both steatosis and denervation. NE levels in the liver were significantly decreased in the steatohepatitis model. Co-culturing WT + WD celiac ganglia with KMs caused denervation that was reversed by anti-TNF⍺ antibodies⁶. NE reduced TNF⍺ mRNA expression in KMs, indicating an anti-inflammatory role. NE increased p-AKT and p-S6K expression in WT + WD hepatocytes, indicating that NE promotes insulin responsiveness. Conclusion: NAergic hyperactivity promotes HLA and portal hypertension via TNF⍺-mediated sympathetic nerve fiber injury. The resulting neuropathy decreases NE levels in the liver, creating a pro-inflammatory, insulin-resistant state.

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3. Wang Z, Liang X, Lu Y, et al. Insomnia Promotes Hepatic Steatosis in Rats Possibly by Mediating Sympathetic Overactivation. Front Physiol. 2021;12(September):1-11. doi:10.3389/fphys.2021.734009
4. Choi IY, Chang Y, Kang G, et al. Low heart rate variability from 10-s electrocardiograms is associated with development of non-alcoholic fatty liver disease. Sci Rep. 2022;12(1):1- 10. doi:10.1038/s41598-022-05037-w
5. Adori C, Daraio T, Kuiper R, et al. Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. Sci Adv. 2021;7(30):1-22. doi:10.1126/sciadv.abg5733
6. Liu K, Yang L, Wang G, et al. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab. 2021;33(3):666-675.e4. doi:10.1016/j.cmet.2021.01.012