Increased miR-34a mediates pathophysiological communication between hepatocytes and HSCs in liver fibrosis. (IMAGE)
Caption
Increased miR-34a induced by obesity and high-fat diet enhances hepatic de novo lipogenesis and disturbs biosynthesis of very-low density lipoprotein metabolism via down-regulation of Mttp, ApoB, and ApoE, leading to the accumulation of lipids in the liver (steatosis). Lipotoxicity derived from the accumulated lipids further induces ER stress and activates metabolic inflammation in the liver, driving the progressive liver injury to MASH, characterized by the activation of TNFα, IL-1β, and CREBH, hepatocyte ballooning, and fibrogenic genes. Simultaneously, secreted miR-34a from the damaged hepatocytes contributes to HSC activation and the subsequent induction of fibrogenic signaling molecules, such as α-SMA, Col1A1, and TGF-β, promoting ECM remodeling and the development of liver fibrosis. TNFα, tumor necrosis factor-alpha; ApoB, apolipoprotein B; ApoE, apolipoprotein E; Mttp, microsomal triglyceride transfer protein; Il-1β, interleukin-1β; CREBH, cAMP-responsive element binding protein H; TGF-β, transforming growth factor-beta; HSC, hepatic stellate cell; COL1A1, collagen type I alpha 1 chain; MASH, metabolic dysfunction-associated steatohepatitis; α-SMA, alpha-smooth muscle actin; ER, endoplasmic reticulum; ECM, extracellular matrix.
Credit
Qihua Duan, Ruixiang Hu, Yan Chen, Henry Wade, Szczepan Kaluzny, Bingrui Zhang, Rongxue Wu, Guangnan Liu, Cunchuan Wang, Edward N. Harris, Qiaozhu Su
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