Hepatic connexin 32 associates with nonalcoholic fatty liver disease severity

Abstract

Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet‐induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786‐797)

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation

“…Furthermore, after establishing the importance of cGAS in ALD, we were able to identify the critical role of Cx32, a known modulator of the intercellular transfer of cGAS-produced 2′3′-cGAMP (15,16). Previous work has established the important role of Cx32 in the inflammatory process of a variety of liver diseases, including drug-induced liver injury, nonalcoholic fatty liver disease, and ischemia-reperfusion injury (17)(18)(19). In the only published study of hepatic gap junctions in ALD, investigators examined the association of Cx32 in alcohol-related hepatocellular carcinoma and did not focus on inflammation (23).…”

“…Although these investigations were limited to in vitro models, recent in vivo studies have highlighted the importance of gap junctions in establishing liver injury. For example, deficiency in connexin 32 (Cx32), the predominant hepatic gap junction, attenuates injury in several murine models of liver disease (17)(18)(19). Despite these compelling data, the role of Cx32 in ALD and its ability to modulate IRF3 in vivo have not been studied.…”

Collagen I Modifies Connexin-43 Hemichannel Activity via Integrin α2β1 Binding in TGFβ1-Evoked Renal Tubular Epithelial Cells

“…Connexin mediated communication has been associated with fibrosis in various tissue types [ 13 , 31 , 32 , 33 , 34 ], with ECM remodelling recorded in multiple models of kidney injury. Several studies identify connexin-43 (Cx43) in the underlying pathology of both glomerular [ 35 ] and tubule disease [ 8 ], where severity of fibrosis in the kidney tubules dictates disease progression [ 36 ].…”

Proteomic screening of plasma identifies potential noninvasive biomarkers associated with significant/advanced fibrosis in patients with nonalcoholic fatty liver disease

“…methods [2][3][4][5][6][7][8][9][10][11][12], including imaging modalities [13][14][15][16][17], biomarkers [18][19][20][21][22][23][24][25][26], and artificial intelligence algorithms [27][28][29][30][31][32].…”