Amino acid is a major carbon source for hepatic lipogenesis

Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.

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Publication Details

Journal
Cell Metabolism
Published
2024-10-25
DOI
https://doi.org/10.1016/j.cmet.2024.10.001
Citations
83
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
32.09
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article

Amino acid is a major carbon source for hepatic lipogenesis

Fangfang Sun, Weiping Han, Xiaojie Bai, Suneng Fu et al.
83 citations
Cell Metabolism
Liver Disease Diagnosis and Treatment
32.09
article

Amino acid is a major carbon source for hepatic lipogenesis

Fangfang Sun, Weiping Han, Xiaojie Bai, Suneng Fu, Haipeng Huang, Yahong Zhang, Lei Liu, Chenchen Jin, Xia Xiao, Jingyun Sun, Honghao Li, Yilie Liao, Qishan Chen, Jia Li
article en
83 citations

Abstract

Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.

Cell MetabolismVol. 36(11)
Agency for Science, Technology and Research (SG), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Cornell University (US), Guangzhou Experimental Station (CN), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), Shanghai Institute of Materia Medica (CN), Center for Life Sciences (CN), Institute of Molecular and Cell Biology (SG), Tsinghua University (CN)
Openalex Percentile: Top 0%
Liver Disease Diagnosis and Treatment
32.09
DOIOpen Access PDFOpenAlex
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