Molecular metabolism · 2026
Hyperactive mTORC1 underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency.
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Alowaisi Amany A, Mahoney Jolonda C, Huo Ran, Berdaweel Islam A, Crawford Rachel M, Mallaro Kendall J, McLendon Jared M, Anderson Ethan J
Аннотация
BACKGROUND: Prohibitins-1,2 (PHB1,2) are highly conserved and ubiquitously expressed proteins that form a multimeric ring complex within mitochondrial and plasma membranes where they intimately control cellular growth and metabolism. Prior studies in clinical and experimental models have linked PHB1 deficiency in liver with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), in addition to MASH and hepatocellular carcinoma, though mechanisms remain poorly understood.
METHODS & RESULTS: Mice with hepatocyte-specific PHB1 haploinsufficiency (hPHB1-KD) were maintained on a standard chow diet. Compared with wild-type (WT), male hPHB1-KD mice at 6 months exhibited moderate but significant increases in body fat, systemic insulin resistance and characteristics of MASLD, while female hPHB1-KD mice were unaffected. Comprehensive transcript-/metabolomic analysis of liver tissue in the male hPHB-KD mice revealed up-regulation of glycerolipid metabolism and Lpin1, a phosphatidic acid phosphatase regulated by mTORC1 that critically regulates hepatic lipid metabolism. Markers of mTORC1 activation were increased in liver from male and female hPHB1-KD mice in the fasted state, accompanied by lower AMPKα phosphorylation, and were not responsive to insulin. PHB1 knockdown experiments in AML12 hepatocytes showed that lipid droplet accumulation occurred in parallel with increased cytosolic, but not nuclear, lipin-1 expression. Notably, short-term treatment with mTORC1 inhibitor Torin1 ameliorated liver steatosis and normalized mTORC1 signaling in male hPHB1-KD mice.
CONCLUSIONS: These findings illustrate novel mechanisms by which PHB1 regulates lipid metabolism and glycemic control in the liver, and further reveal a sex dimorphic role for mTORC1 hyperactivation in pathogenesis of MASLD.
METHODS & RESULTS: Mice with hepatocyte-specific PHB1 haploinsufficiency (hPHB1-KD) were maintained on a standard chow diet. Compared with wild-type (WT), male hPHB1-KD mice at 6 months exhibited moderate but significant increases in body fat, systemic insulin resistance and characteristics of MASLD, while female hPHB1-KD mice were unaffected. Comprehensive transcript-/metabolomic analysis of liver tissue in the male hPHB-KD mice revealed up-regulation of glycerolipid metabolism and Lpin1, a phosphatidic acid phosphatase regulated by mTORC1 that critically regulates hepatic lipid metabolism. Markers of mTORC1 activation were increased in liver from male and female hPHB1-KD mice in the fasted state, accompanied by lower AMPKα phosphorylation, and were not responsive to insulin. PHB1 knockdown experiments in AML12 hepatocytes showed that lipid droplet accumulation occurred in parallel with increased cytosolic, but not nuclear, lipin-1 expression. Notably, short-term treatment with mTORC1 inhibitor Torin1 ameliorated liver steatosis and normalized mTORC1 signaling in male hPHB1-KD mice.
CONCLUSIONS: These findings illustrate novel mechanisms by which PHB1 regulates lipid metabolism and glycemic control in the liver, and further reveal a sex dimorphic role for mTORC1 hyperactivation in pathogenesis of MASLD.