Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease

Abstract

Objective Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice and patients with non-alcoholic steatohepatitis (NASH), yet hepatocyte miR-34a's role in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated. Methods Mice overexpressing or deficient in hepatocyte miR-34a and control mice were fed a diet enriched in fats, cholesterol, and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression, and reversal of NAFLD was determined. Results The hepatocyte-specific expression of miR-34a aggravated HFCF diet-induced NAFLD. In contrast, germline or adult-onset deletion of hepatocyte miR-34a attenuated the development and progression of NAFLD. In addition, pharmacological inhibition of miR-34a reversed HFCF diet-induced steatohepatitis. Mechanistically, hepatocyte miR-34a regulated the development and progression of NAFLD by inducing lipid absorption, lipogenesis, inflammation, and apoptosis but inhibiting fatty acid oxidation. Conclusions Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD.

Concerted regulation of non-alcoholic fatty liver disease progression by microRNAs in apolipoprotein E-deficient mice

“…This result is of importance as Adipor2 acts as a regulator of glucose and lipid metabolism through modulating the peroxisome proliferator-activated receptor alpha (PPARα) pathway ( Lei et al, 2018 ). As other authors have checked in vivo and in vitro ( Choi et al, 2013 ; Fu and Kemper, 2016 ; Xu et al, 2021b ), another miRNA that regulates this gene is miR-34a, which is also overexpressed in our model. This miRNA is altered in NAFLD and other related diseases, such as obesity and atherosclerosis.…”

“…This miRNA is altered in NAFLD and other related diseases, such as obesity and atherosclerosis. Its expression is triggered by lipids and aggravates NAFLD and NASH, either by impairing lipid accumulation, promoting oxidative stress or fostering hepatocyte apoptosis ( Lee et al, 2010 ; Castro et al, 2013 ; Choi et al, 2013 ; Zhang et al, 2020 ; Xu et al, 2021a , b ). The regulation of Adipor2 by miR-34a induces ectopic deposition of lipids and decreases mitochondrial content by resistin action through the AMP-activated protein kinase (AMPK)/PPARα pathway ( Wen et al, 2018 ).…”

Neochlorogenic Acid Attenuates Hepatic Lipid Accumulation and Inflammation via Regulating miR-34a In Vitro

“…miR-34a has been demonstrated to be a critical regulator of lipid metabolism [ 16 ]. In the current study, Figure 7 A demonstrates that OA induced miR-34a expression, which was reduced upon co-treatment with 5-CQA.…”

“…miR-34a has multiple roles in the regulation of cell cycle, apoptosis, and differentiation. In addition, increasing the expression of miR-34a has been indicated to lead to NAFLD development [ 15 , 16 ]. Thus, miR-34a is implied to be a useful target for alleviating lipid-associated metabolic diseases.…”

Targeting T Cell Subtypes for NAFLD and NAFLD-Related HCC Treatment: An Opinion

“…Overexpression of microRNA-195 (miR-195) can improve the balance of Th17/Treg via regulating CD40 expression in rat liver tissues, accompanying decrease of serum level of proinflammatory cytokines (e.g., TNF-α), total cholesterol (TC) and triglyceride (TG), liver injury markers aspartate transaminase (AST), and alanine aminotransferase (ALT) ( 61 ). In addition, hepatocyte-specific overexpression of miR-34a promoted high cholesterol and fructose (HFCF) fat diet-induced NAFLD in mice, while pharmaceutical suppression of miR-34a can reverse NAFLD progression ( 62 ). miR-26a can inhibit hepatic expression of IL-17 and IL-6, as lentiviral vector delivered miR-26a treatment significantly decreased total liver weight, liver deposition of TG, and serum ALT concentration compared lentiviral control-treated mice, accompanying decreased infiltration of γδ T cells, and granulocyte-differentiation antigen-1 (Gr-1) + cells and CD11b + cells ( 63 ).…”