Apolipoprotein A4 Restricts Diet‐Induced Hepatic Steatosis via SREBF1‐Mediated Lipogenesis and Enhances IRS‐PI3K‐Akt Signaling

• Published in: Molecular nutrition & food research 2022-09, Vol.66 (18), p.e2101034-n/a
• Main Authors: Cheng, Cheng, Liu, Xiao‐Huan, He, Jing, Gao, Jing, Zhou, Jin‐Ting, Fan, Jing‐Na, Jin, Xi, Zhang, Jianbo, Chang, Liao, Xiong, Zijun, Yu, Jun, Li, Shengbin, Li, Xiaoming
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adipocytes; AKT protein; Apolipoprotein A4; Diet; Fatty acids; Fatty liver; Gene expression; Glucose; Hemostasis; Hemostatics; hepatic steatosis; Hepatocytes; Insulin; Insulin resistance; Insulin secretion; Lipogenesis; Lipolysis; Liver; Metabolic disorders; Metabolic syndrome; Obesity; Oxidation; Resistance factors; Risk analysis; Risk factors; Sensitivity; Signal transduction; Signaling; SREBF1; Steatosis; Therapeutic targets
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.202101034

Scope Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose‐stimulated insulin secretion and glucose uptake via PI3K‐Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear. Methods and results ApoA4‐knockout (KO) aggravates diet‐induced obesity, hepatic steatosis, and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA‐seq data. Conversely, liver‐specific overexpression of ApoA4 via AAV‐ApoA4 transduction reverses the effect in ApoA4‐KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short‐term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS‐PI3K‐Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity. Conclusion ApoA4 restricts hepatic steatosis by inhibiting SREBF1‐mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS‐PI3K‐Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity‐associated NAFLD. ApoA4 deletion aggravates HFD‐induced murine obesity, insulin resistance, and hepatic steatosis. Liver‐specific overexpression of ApoA4 via AAV‐ApoA4 transduction, or short‐term treatment with recombinant ApoA4 protein reverse the effects. Together with the studies on primary cultured hepatocytes and a cell line, we suggest that ApoA4 has an insulin‐like action via the IRS‐PI3K‐Akt pathway and restricts hepatic steatosis by inhibiting SREBF1‐mediated lipogenesis.