Liu Jie, Oliverio Anna, Godlewski Grzegorz, Kočvarová Radka, Arif Muhammad, Basu Abhishek, Guan Yukun, Feng Dechun, Puhl Henry L, Iyer Malliga R, Cinar Resat, Gao Bin, Tam Joseph, Kunos George
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
Metabolism. 2025 Sep;170:156308. doi: 10.1016/j.metabol.2025.156308. Epub 2025 May 28.
Obesity-induced steatotic liver disease (SLD) is driven by the uptake of adipocyte-derived fatty acids (FAs) into hepatocytes via the FA translocase CD36, which also prevents their consumption by inhibiting AMP kinase (AMPK)-mediated FA oxidation (FAO). We explored the role of hepatocyte CB1 receptors (hCB1R) in controlling hepatic triglyceride (TG) content by regulating CD36 and its downstream targets.
hCB1R knockout (hCB1Rko) mice and their control littermates kept on standard or high-fat diet were used to analyze hCB1R-mediated hepatic gene expression profile and lipid metabolism in intact mice and in cultured hepatocytes.
Multi-omics data indicate that hCB1R target a distinct set of genes associated with SLD, including Cd36. In mice with diet-induced obesity, hCB1R signaling via CD36-AMPK-FAO pathway contributes to both the development of SLD and its reversal by CB1R blockade. But, in lean mice hCB1R signaling inhibits CD36 expression and activates AMPK-mediated FAO. These opposite effects were replicated in AML12 mouse hepatocytes incubated with or without oleic acid (OA). OA, an endogenous ligand of GPR3, induced a switch in hCB1R signaling from a Gα-mediated reduction in cAMP to a Gα-mediated increase in cAMP in a GPR3/Gα -dependent manner, facilitated by increasing the ratio of Gα:Gα proteins in the steatotic compared to lean liver.
In the lean state, endocannabinoid activation of hCB1R increases FAO, which mitigates SLD, as reported for chronic marihuana smokers, whereas in obese mice hCB1R tonically inhibit FAO, which promotes SLD and underlies the anti-steatotic effect of peripheral CB1R blockade.
肥胖诱导的脂肪性肝病（SLD）是由脂肪细胞衍生的脂肪酸（FAs）通过脂肪酸转运蛋白CD36进入肝细胞所驱动的，CD36还通过抑制AMP激酶（AMPK）介导的脂肪酸氧化（FAO）来阻止脂肪酸的消耗。我们探讨了肝细胞CB1受体（hCB1R）通过调节CD36及其下游靶点在控制肝脏甘油三酯（TG）含量中的作用。
使用hCB1R基因敲除（hCB1Rko）小鼠及其作为对照的同窝小鼠，分别给予标准饮食或高脂饮食，以分析hCB1R介导的完整小鼠和培养肝细胞中的肝脏基因表达谱及脂质代谢。
多组学数据表明，hCB1R靶向一组与SLD相关的独特基因，包括Cd36。在饮食诱导肥胖的小鼠中，通过CD36-AMPK-FAO途径的hCB1R信号传导既有助于SLD的发展，也参与了CB1R阻断对其的逆转作用。但是，在瘦小鼠中，hCB1R信号传导抑制CD36表达并激活AMPK介导的FAO。在用油酸（OA）或不用油酸孵育的AML12小鼠肝细胞中，也观察到了这些相反的作用。OA是GPR3的内源性配体，它以GPR3/Gα依赖性方式诱导hCB1R信号从Gα介导的cAMP减少转变为Gα介导的cAMP增加，与瘦肝脏相比，脂肪变性肝脏中Gα:Gα蛋白比例的增加促进了这种转变。
在瘦状态下，内源性大麻素对hCB1R的激活增加了FAO，从而减轻了SLD，这与慢性大麻吸烟者的情况一致；而在肥胖小鼠中，hCB1R持续抑制FAO，促进了SLD的发展，这也是外周CB1R阻断具有抗脂肪变性作用的基础。
