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Review
. 2023 May;43(2):149-162.
doi: 10.1055/s-0043-57237. Epub 2023 May 8.

Hepatic Innervations and Nonalcoholic Fatty Liver Disease

Monika Adori  1 , Sadam Bhat  2 , Roberto Gramignoli  3 , Ismael Valladolid-Acebes  4 , Tore Bengtsson  5 , Mathias Uhlèn  6   7 , Csaba Adori  5   6
Affiliations
Review

Hepatic Innervations and Nonalcoholic Fatty Liver Disease

Monika Adori et al. Semin Liver Dis. 2023 May.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.

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Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
Sympathetic innervation of the mouse and human liver. ( A ) Periportal sympathetic nerves in the mouse liver are visualized by tyrosine hydroxylase (TH) volume immunostaining. Left panel : TH staining; middle panel : elements of the portal triad are segmented and color-coded based on autofluorescence; right panel : sympathetic nerves around the segmented elements of the portal triad. ( B ) TH volume immunostaining of a 5 × 5 × 2 mm piece of healthy human liver. Note the extensive thick nerve fibers around the portal triad and the interlobular branches ( arrows ) that arise from the periportal nerve plexus. From these interlobular nerves, fine intraparenchymal fibers target the parenchyma. (Micrographs are from Adori et al. 22 )
Fig. 2
Fig. 2
Sympathetic nerve pathology in experimental and human nonalcoholic fatty liver disease (NAFLD). ( A, B ) tyrosine hydroxylase (TH) volume immunostaining in control mouse liver (A–A′) and in experimental steatohepatitis (B–B′). Boxes in A and B indicated with a′ and b′ are enlarged in A′ and B′, respectively. Note the extensive fiber degeneration in NASH. TH immunostaining in control mouse ( C ) and in experimental steatosis ( D ). Note the ectopic, parenchymal sprouting of noradrenergic fibers in steatosis ( arrowheads in D ). ( E ) Sympathetic nerve pathology in human NAFLD. Intraparenchymal fine fibers are gradually degenerating and disappearing with the more severe NAFLD pathology. ORO-red: Oil Red O lipid staining. (Micrographs are from Adori et al, with slight modifications.)
Fig. 3
Fig. 3
Portal vein stenosis in experimental steatohepatitis and its spatial correlation with the remaining sympathetic nerves. ( A, B ) Liver vasculature in steatohepatitic mouse is visualized by inverted autofluorescence (AF) in 3D ( gray channel in A and B ). Portal vein stenotic alteration is correlating with the extension of the already degenerating noradrenergic nerve fibers (tyrosine hydroxylase [TH] volume immunostaining, red channel in B). Yellow dashed lines indicate the end of TH + innervations. (Micrographs are from Adori et al. 22 )
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References

    1. Kaya E, Yılmaz Y. Non-alcoholic fatty liver disease: a growing public health problem in Turkey. Turk J Gastroenterol. 2019;30(10):865–871. - PMC - PubMed
    1. Younossi Z M. Non-alcoholic fatty liver disease - a global public health perspective. J Hepatol. 2019;70(03):531–544. - PubMed
    1. Yeh M M, Brunt E M. Pathology of nonalcoholic fatty liver disease. Am J Clin Pathol. 2007;128(05):837–847. - PubMed
    1. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10(04):284–296. - PubMed
    1. Mantovani A, Scorletti E, Mosca A, Alisi A, Byrne C D, Targher G. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism. 2020;111S:154170. - PubMed
-