Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5622, USA.
Gastroenterology. 2010 Apr;138(4):1607-17. doi: 10.1053/j.gastro.2009.12.055. Epub 2010 Jan 11.
BACKGROUND & AIMS: Mallory-Denk bodies (MDBs) are keratin (K)-rich cytoplasmic hepatocyte inclusions commonly associated with alcoholic steatohepatitis. Given the significant gender differences in predisposition to human alcohol-related liver injury, and the strain difference in mouse MDB formation, we hypothesized that sex affects MDB formation.
MDBs were induced in male and female mice overexpressing K8, which are predisposed to MDB formation, and in nontransgenic mice by feeding the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDB presence was determined by histologic, immunofluorescence, and biochemical analyses and correlated to liver injury using serologic and pathologic markers. Cytoskeletal and metabolic liver protein analysis, in vitro metabolism studies, and measurement of oxidative stress markers and protoporphyrin-IX were performed.
Male mice formed significantly more MDBs, which was attenuated modestly by estradiol. MDB formation was accompanied by increased oxidative stress. Female mice had significantly fewer MDBs and oxidative stress-related changes, but had increased ductular reaction protoporphyrin-IX accumulation, and MDB-preventive K18 induction. Evaluation of the microsomal cytochrome-P450 (CYP) enzymes revealed significant gender differences in protein expression and activity in untreated and DDC-fed mice, and showed that DDC is metabolized by CYP3A. The changes in CYPs account for the gender differences in porphyria and DDC metabolism. DDC metabolite formation and oxidative injury accumulate on chronic DDC exposure in males, despite more efficient acute metabolism in females.
Gender dimorphic formation of MDBs and porphyria associate with differences in CYPs, oxidative injury, and selective keratin induction. These findings may extend to human MDBs and other neuropathy- and myopathy-related inclusions.
Mallory-Denk 小体（MDB）是富含角蛋白（K）的细胞质肝细胞包涵物，通常与酒精性脂肪性肝炎有关。鉴于性别差异对人类酒精性肝损伤的易感性以及小鼠 MDB 形成的品系差异，我们假设性别会影响 MDB 的形成。
通过给予卟啉原化合物 3,5-二乙氧羰基-1,4-二氢吡啶（DDC），在过表达 K8 的雄性和雌性小鼠以及非转基因小鼠中诱导 MDB 形成，K8 易形成 MDB。通过组织学、免疫荧光和生化分析确定 MDB 的存在，并使用血清学和病理学标志物将其与肝损伤相关联。进行细胞骨架和代谢性肝蛋白分析、体外代谢研究以及测量氧化应激标志物和原卟啉-IX。
雄性小鼠形成的 MDB 明显更多，而雌二醇可适度减轻。MDB 的形成伴随着氧化应激的增加。雌性小鼠的 MDB 和与氧化应激相关的变化明显较少，但胆管反应原卟啉-IX 积累和 MDB 预防性 K18 诱导增加。对微粒体细胞色素 P450（CYP）酶的评估显示，未处理和 DDC 喂养的小鼠中存在明显的性别差异的蛋白表达和活性，并且表明 DDC 由 CYP3A 代谢。CYP 的变化解释了卟啉症和 DDC 代谢中的性别差异。尽管女性的急性代谢更有效，但在慢性 DDC 暴露下，DDC 代谢物的形成和氧化损伤在雄性中会累积。
MDB 和卟啉症的性别二态形成与 CYP、氧化损伤和选择性角蛋白诱导的差异相关。这些发现可能扩展到人类的 MDB 和其他与神经病和肌病相关的包涵物。
