Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia

IF 6.3 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2026-02-01 Epub Date: 2025-12-19 DOI:10.1016/j.molmet.2025.102310

Melissa A. Fulham , John D. Griffin , Sylvie Perez , Zhongyuan Sun , Natalie A. Daurio , Gang Xing , Michelle F. Clasquin , Melissa R. Miller , Craig L. Hyde , Scott P. Kelly , Magalie Boucher , Rachel Poskanzer , Ramya Gamini , Evanthia Pashos , Ying Zhang , Elaine Kuang , Josh Fienman , Kendra K. Bence , Gregory J. Tesz

{"title":"Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia","authors":"Melissa A. Fulham , John D. Griffin , Sylvie Perez , Zhongyuan Sun , Natalie A. Daurio , Gang Xing , Michelle F. Clasquin , Melissa R. Miller , Craig L. Hyde , Scott P. Kelly , Magalie Boucher , Rachel Poskanzer , Ramya Gamini , Evanthia Pashos , Ying Zhang , Elaine Kuang , Josh Fienman , Kendra K. Bence , Gregory J. Tesz","doi":"10.1016/j.molmet.2025.102310","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><div>Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.</div></div><div><h3>Methods</h3><div><em>Aldob</em> was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.</div></div><div><h3>Results</h3><div>Deletion of <em>Aldob</em> caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.</div></div><div><h3>Conclusions</h3><div><em>Aldob</em> deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102310"},"PeriodicalIF":6.3000,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212877825002170","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/12/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

Objectives

Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.

Methods

Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.

Results

Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.

Conclusions

Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.

查看原文本刊更多论文

遗传性果糖不耐受患者的肝脏代谢受损会增加脂肪变性和高甘油三酯血症的果糖不依赖型风险。

目的：遗传性果糖不耐受（HFI）是一种罕见的遗传性疾病，由醛脲酶B缺乏引起，果糖暴露会导致严重的代谢病变，包括2型糖尿病和肝脏脂肪变性。尽管坚持无果糖饮食，一些人仍然出现疾病。使用HFI的大鼠模型，我们证明果糖独立的病理存在，并确定驱动疾病的分子途径。方法：利用crispr /Cas9 （Aldob - ko）基因对Sprague Dawley大鼠的Aldob基因进行删除。进行表型、代谢组学和转录组学研究以确定促进果糖独立病理的机制。使用药理学抑制剂和aso检测潜在的分子原因。结果：Aldob缺失导致低果糖饲料断奶大鼠肝脏脂肪变性、纤维化和生长发育迟缓，再现了人类HFI。在无果糖食物中，AldoB-KO大鼠表型正常。然而，在禁食时，雄性和雌性AldoB-KO大鼠由于脂肪酸氧化（FAOx）受损和新生脂肪生成（DNL）升高而发生肝脏脂肪变性和高脂血症。转录和代谢组学分析显示，AldoB-KO大鼠肝脏碳水化合物反应元件结合蛋白（ChREBP）的激活增加是由于糖异生损伤引起的糖酵解代谢物积累。乙酰辅酶a羧化酶（ACC）和二酰基甘油酰基转移酶2 （DGAT2）抑制剂治疗可降低AldoB-KO大鼠的肝脏脂质和血浆甘油三酯。最后，通过电子健康记录，我们观察到HFI患者中代谢功能障碍相关脂肪性肝炎（MASH）的诊断增加。结论：Aldob缺失引起大鼠空腹时果糖非依赖型高脂血症和脂肪变性。患有HFI的个体即使在果糖戒断后也可能有肝脏疾病和高脂血症的风险，这表明可能需要额外的治疗来减轻疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.