Fig. 1: Simultaneous deregulation of nutrient and hormone signaling to mTORC1 leads to synergic liver damage, glucose metabolism alteration and decreased lifespan.

A Liver weight of 10- to 26-week-old wild-type (n = 9), Li-RagA^GTP (n = 9), Li-TSC1^KO (n = 9) and Li-TSC1^KORagA^GTP (n = 9) male and female mice. Statistical significance was calculated by using 1way ANOVA with Tukey’s multiple comparisons test. B Levels of circulating alkaline phosphatase (ALP), alanine aminotransferase (ALT), bile acids, bilirubin and cholesterol were measured in 9- to 25-week-old wild-type (n = 8), Li-RagA^GTP (n = 7), Li-TSC1^KO (n = 8) and Li-TSC1^KORagA^GTP (n = 10) male and female mice. Values were made relative to wild-type average level and presented in log₁₀ scale. Statistical significance was calculated by using 2way ANOVA with Tukey’s multiple comparisons test. C Representative hepatic H&E, Sirius red staining and CD45 IHC of 10- to 26-week-old wild-type, Li-RagA^GTP, Li-TSC1^KO and Li-TSC1^KORagA^GTP male and female mice. Black, green and red arrowheads indicate necrotic, fibrotic and inflammatory areas, respectively. Scale bar 100 μm. D Quantification of necrosis, fibrosis and inflammation in 10- to 26-week-old wild-type (necrosis n = 4, fibrosis/inflammation n = 6), Li-RagA^GTP (necrosis n = 4, fibrosis/inflammation n = 2), Li-TSC1^KO (necrosis/fibrosis/inflammation n = 4) and Li-TSC1^KORagA^GTP (necrosis n = 3, fibrosis/inflammation n = 4) male and female mice. Statistical significance was calculated by using 2way ANOVA with Tukey’s multiple comparisons test. E Glucose tolerance test (GTT) of 8- to 16-week-old wild-type (n = 25), Li-RagA^GTP (n = 7), Li-TSC1^KO (n = 7) and Li-TSC1^KORagA^GTP (n = 6) females and area under the curve (AUC) of glucose tolerance test. Statistical significance was calculated by using 1way ANOVA with Tukey’s multiple comparisons test. F, G Kaplan–Meier survival curves of wild-type (n = 48 males, n = 38 females), Li-TSC1^KO (n = 19 males, n = 20 females) and Li-TSC1^KORagA^GTP (n = 34 males and n = 21 females) male and female mice, respectively. Mean survival depicted in green for Li-TSC1^KO and blue for Li-TSC1^KO RagA^GTP. Mean survival of Li-RagA^GTP mice from ref. ¹⁷ is depicted in pink. Statistical significance was calculated with the log-rank (Mantel–Cox) test. H Heterogeneous liver tumor development in wild-type (n = 41), Li-RagA^GTP (n = 33), Li-TSC1^KO (n = 11) and Li-TSC1^KORagA^GTP (n = 18) male and female mice. Statistical significance was calculated with chi-squared test. In all panels data are presented as mean values ± standard deviation.