Background and Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. Methods C57BL/6 mice were subjected to short-term (10-days) ethanol-plus-one binge or long- term (8-weeks) ethanol-plus-multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Compared to young (8–12 weeks) mice, middle-aged (12–14 months) and old (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term-plus-one binge or long-term-plus-multiple binges of ethanol feeding. Long-term-plus- multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of Sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term-plus-binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to short-term-plus-binge ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD.
The thyroid functions of breastfed infants, as well as (indirectly) the development of their central nervous system, are dependent on the iodine status of the lactating mother. Purkinje cell protein-2 is a cell-specific marker of the cerebellum Purkinje cell and is a suitable indicator for observing the postnatal development of the cerebellum after birth. We measured the Purkinje cell protein-2 mRNA and protein levels in the rat cerebellum in the critical postnatal (14 days after birth) and maturation periods (28 days after birth) to determine the effect of different nutritional iodine levels on cerebellum growth in the offspring during lactation. We found that severe iodine deficiency resulted in thyroid dysfunction in lactating rats and their offspring on both 14 and 28 days, showing maternal total T(4) 16.7 ± 12.0 vs 36.4 ± 15.0, P < 0.05 (14 days) and 22.6 ± 18.7 vs 53.4 ± 9.4, P < 0.01 (28 days), and neonatal total T(4) 10.6 ± 2.3 vs 16.4 ± 4.7, P < 0.01(14 days) and 12.8 ± 2.9 vs 16.7 ± 3.4, P < 0.05 (28 days), respectively. The Purkinje cell protein-2 mRNA and its protein levels in offspring rats were significantly reduced that showed Purkinje cell protein-2 mRNA 1.12 ± 0.04 vs 2.25 ± 0.53, P < 0.05 (14 days) and 1.74 ± 0.94 vs 8.69 ± 2.71, P < 0.01 (28 days). However, mild iodine deficiency and excessive iodine maintained almost normal thyroid function in maternal and neonatal rats and normal Purkinje cell protein-2 mRNA and protein levels in offspring's cerebellum. We conclude that severe iodine deficiency could significantly reduce Purkinje cell protein-2 mRNA and its protein levels, indicating that the cerebellum development was retarded, but mild iodine deficiency and excessive iodine could maintain them at an approximately normal level by the mother's and offspring's compensations, especially by the mother's mammary glands.
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