Trajectories of Liver Fibrosis and Gene Expression Profiles in Nonalcoholic Fatty Liver Disease Associated With Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. 9; pp. 1297 - 1306
• Main Authors: Sako, Saori, Takeshita, Yumie, Takayama, Hiroaki, Goto, Hisanori, Nakano, Yujiro, Ando, Hitoshi, Tsujiguchi, Hiromasa, Yamashita, Tatsuya, Arai, Kuniaki, Kaneko, Shuichi, Nakamura, Hiroyuki, Harada, Kenichi, Honda, Masao, Takamura, Toshinari
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.09.2023
• Subjects: Biopsy; Cell activation; Diabetes; Diabetes mellitus; Endothelial cells; Fatty liver; Fibrosis; Gene expression; Hepatocytes; Hypoxia; Liver diseases; Oxidative stress; Plasma cells; Steatosis; Stellate cells; Therapeutic targets
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db22-0933

Understanding the mechanisms linking steatosis to fibrosis is needed to establish a promising therapy against nonalcoholic fatty liver disease (NAFLD). The aim of this study was to clarify clinical features and hepatic gene expression signatures that predict and contribute to liver fibrosis development during the long-term real-world histological course of NAFLD in subjects with and without diabetes. A pathologist scored 342 serial liver biopsy samples from 118 subjects clinically diagnosed with NAFLD during a 3.8-year (SD 3.45 years, maximum 15 years) course of clinical treatment. At the initial biopsy, 26 subjects had simple fatty liver, and 92 had nonalcoholic steatohepatitis (NASH). In the trend analysis, the fibrosis-4 index (P < 0.001) and its components at baseline predicted the future fibrosis progression. In the generalized linear mixed model, an increase in HbA1c, but not BMI, was significantly associated with fibrosis progression (standardized coefficient 0.17 [95% CI 0.009–0.326]; P = 0.038) for subjects with NAFLD and diabetes. In gene set enrichment analyses, the pathways involved in zone 3 hepatocytes, central liver sinusoidal endothelial cells (LSECs), stellate cells, and plasma cells were coordinately altered in association with fibrosis progression and HbA1c elevation. Therefore, in subjects with NAFLD and diabetes, HbA1c elevation was significantly associated with liver fibrosis progression, independent of weight gain, which may be a valuable therapeutic target to prevent the pathological progression of NASH. Gene expression profiles suggest that diabetes-induced hypoxia and oxidative stress injure LSECs in zone 3 hepatocytes, which may mediate inflammation and stellate cell activation, leading to liver fibrosis.