Journal Article

Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue

Son, Sae-Mi, Oh, Hyunhee, Cho, Yoonil, Lee, Se-Jin, Jung, Sungwon, Hur, Jang Ho, Kim, Il-Young, Choi, Cheol Soo, Kim, Yeongmin, Park, Shi-Young, Park, Sanghee, Lee, Hui-Young

2025

Overview

Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe -knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD. Activin E protects against fatty liver by inhibiting fat breakdown Hepatic endoplasmic reticulum (ER) stress is associated with nonalcoholic fatty liver disease (NAFLD). Although it is known that the liver’s ER can activate defense mechanisms to slow NAFLD progression, the specific protective processes remain unclear. Recent studies have identified activin E, encoded by the Inhbe gene, as being linked to metabolic conditions such as insulin resistance and NAFLD. This research demonstrates that hepatic Inhbe expression increases during ER stress, a process regulated by ATF4. Loss of Inhbe led to severe hepatic steatosis due to enhanced lipolysis in adipose tissue. By contrast, hepatic overexpression of Inhbe alleviated hepatic steatosis by suppressing adipose tissue lipolysis through ALK7–Smad signaling. These findings suggest that activin E functions as a regulatory hepatokine, protecting against NAFLD by preventing excessive fatty acid influx into the liver through the inhibition of adipose lipolysis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/21 / 38/89 / 631/443/319/1642/2037 / 631/443/319/2723 / 64/60 / 692/163/2743/2037 / 692/699/2743/2037 / 82/58 / 96/1 / 96/109 / Activating Transcription Factor 4 - genetics / Activating Transcription Factor 4 - metabolism / Activin / Activins - genetics / Activins - metabolism / Adipose tissue / Adipose Tissue, White - metabolism / Animals / Artificial intelligence / Biomedical and Life Sciences / Biomedicine / Body fat / Defense mechanisms / Diet, High-Fat - adverse effects / Disease Models, Animal / Endoplasmic reticulum / Endoplasmic Reticulum Stress / Fatty acids / Fatty liver / Fatty Liver - metabolism / High fat diet / Humans / Inhibin-beta Subunits - genetics / Inhibin-beta Subunits - metabolism / Insulin resistance / Lipid Metabolism / Lipolysis / Liver - metabolism / Liver - pathology / Liver diseases / Male / Medical Biochemistry / Metabolic disorders / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular Medicine / Non-alcoholic Fatty Liver Disease - etiology / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - pathology / Nutrient deficiency / Phenotypes / Smad protein / Steatosis / Stem Cells / Stress response / 생화학