Excessive free fatty acid sensing in pituitary lactotrophs elicits steatotic liver disease by decreasing prolactin levels
Xinlu Ji,
Hongli Yin,
Tianwei Gu,
Hao Xu,
Da Fang,
Kai Wang,
Haixiang Sun,
Sai Tian,
Tianyu Wu,
Yuanyuan Nie,
Pengzi Zhang,
Yan Bi
Affiliations
Xinlu Ji
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Hongli Yin
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Tianwei Gu
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Hao Xu
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Da Fang
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Kai Wang
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Haixiang Sun
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Sai Tian
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Tianyu Wu
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Yuanyuan Nie
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
Pengzi Zhang
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China; Corresponding author
Yan Bi
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China; Corresponding author
Summary: The pituitary is the central endocrine gland with effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, it is not clear whether the pituitary responds to free fatty acid (FFA) toxicity, thus dysregulating hepatic lipid metabolism. Here, we demonstrate that decreased prolactin (PRL) levels are involved in the association between FFA and MASLD based on a liver biospecimen-based cohort. Moreover, overloaded FFAs decrease serum PRL levels, thus promoting liver steatosis in mice with both dynamic diet intervention and stereotactic pituitary FFA injection. Mechanistic studies show that excessive FFA sensing in pituitary lactotrophs inhibits the synthesis and secretion of PRL in a cell-autonomous manner. Notably, inhibiting excessive lipid uptake using pituitary stereotaxic virus injection or a specific drug delivery system effectively ameliorates hepatic lipid accumulation by improving PRL levels. Targeted inhibition of pituitary FFA sensing may be a potential therapeutic target for liver steatosis.
