SULT2A8 is a male-predominant and liver-specific mouse cytosolic sulfotransferase (SULT) that sulfonates 7α-hydroxyl (7α-OH) bile acids in vitro. Sulfonation regulates bile acid homeostasis, which in turn regulates cholesterol and energy metabolism. Using the Sult2a8-heterozygous (HT) mouse model created earlier in our laboratory, we aimed to investigate the physiological role of SULT2A8 in sulfonating 7α-OH bile acids and its impact on energy metabolism in vivo under both fed and energy-deprivation conditions. Disruption of one allele of the Sult2a8 gene in male HT mice resulted in losing ~ 50% of the 7α-OH sulfonating activity compared to wild-type (WT) control, but no significant change in female HT mice. Under the fed condition comparing the levels of hepatic and biliary bile acids as well as plasma/serum energy metabolites, HT mice displayed a profile similar to that of WT mice, suggesting that the Sult2a8-haplodeficient mice conducted normal energy metabolism. However, after 48-h fasting, a significant decrease in plasma cholesterol level was found in male HT mice but without any significant reduction in female HT mice. Of interest, in male Sult2a8-haplodeficient mice, an increase of the hepatic taurine-conjugated cholic acid level was noted but no noticeable change in other tested bile acids after fasting. Taken together, SULT2A8 is a male-specific and key hepatic SULT in metabolizing 7α-OH primary bile acids. During energy deprivation, SULT2A8 is required to maintain the bile acid and cholesterol metabolism, suggesting SULT is a potential therapeutic target for controlling metabolic diseases.

SULT2A8 是一种雄性占优势的肝脏特异性小鼠细胞溶质磺基转移酶 (SULT)，可在体外磺化 7α-羟基 (7α-OH) 胆汁酸。磺化调节胆汁酸稳态，进而调节胆固醇和能量代谢。使用我们实验室早期创建的Sult2a8-杂合 (HT) 小鼠模型，我们旨在研究 SULT2A8 在磺化 7α-OH 胆汁酸中的生理作用及其在进食和能量缺乏条件下对体内能量代谢的影响。Sult2a8的一个等位基因的破坏与野生型 (WT) 对照相比，雄性 HT 小鼠中的 7α-OH 磺化活性降低了约 50%，但雌性 HT 小鼠没有显着变化。在比较肝脏和胆汁酸水平以及血浆/血清能量代谢物的进食条件下，HT 小鼠显示出与 WT 小鼠相似的特征，表明Sult2a8单倍体缺陷小鼠进行了正常的能量代谢。然而，禁食 48 小时后，雄性 HT 小鼠的血浆胆固醇水平显着降低，而雌性 HT 小鼠没有任何显着降低。有趣的是，在男性Sult2a8- 单倍体缺陷小鼠，在禁食后观察到肝脏牛磺酸结合胆酸水平增加，但其他测试的胆汁酸没有明显变化。综上所述，SULT2A8 是一种男性特异性和关键的肝脏 SULT，用于代谢 7α-OH 初级胆汁酸。在能量缺乏期间，需要 SULT2A8 来维持胆汁酸和胆固醇代谢，这表明 SULT 是控制代谢疾病的潜在治疗靶点。