Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency

Abstract

BackgroundCell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl4)-induced liver damage compared to healthy controls (Wt Igf +/+). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/−).MethodsThree groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+) were included in the protocol: untreated controls (Wt). Controls that received CCl4 (Wt + CCl4) and Wt + CCl4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl4 + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/−) groups were studied: untreated Hz, Hz + CCl4, and Hz + CCl4 + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM.ResultsAn altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl4 + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl4. Moreover, there was a correlation between MDA levels and the histological damage score (Pearson’s r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma.ConclusionsIGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1198-4) contains supplementary material, which is available to authorized users.

Low-Level Saturated Fatty Acid Palmitate Benefits Liver Cells by Boosting Mitochondrial Metabolism via CDK1-SIRT3-CPT2 Cascade

“…Using GFP-labeled mitochondrial proteins and transmission electron microscopy, we showed that mitochondrial mass and ultrastructural integrity were markedly protected in LPA-pretreated cells compared to the control cells without LPA pretreatment (Figure S4D). LPA-mediated hepatoprotective function was then tested using the established mouse model of CCl 4 -induced acute liver injury (Morales-Garza et al, 2017). The most effective in vivo PA concentration was determined based on tests in mice showing that intragastric gavage with 0.5 mg/mL of PA, but not 5.0 mg/mL or 100 mg/mL, increased mitochondrial Dcm and reduced O 2 À in the liver (Figure S5A).…”

Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

“…Interestingly, mice with a liver-specific IGF-1R knockout also displayed a strong impairment in hepatocyte proliferation and regeneration after partial hepatectomy [ 49 ]. Furthermore, a recent study by Morales-Garza et al demonstrated that IGF-1-deficient mice showed a reduced total liver weight on postnatal day 11, whereas subcutaneous IGF-1 administration attenuated this growth retardation, highlighting the important role of IGF-1 in liver growth [ 50 ]. However, these data are only in part comparable to our present experimental model, in which we expose the liver during fetal development and during the postnatal period to an adverse metabolic microenvironment.…”

Lack of Mof reduces acute liver injury by enhancing transcriptional activation of Igf1

“…Existing experiments have also proved that IGF‐1 relieves the premature senescence of liver cells during liver injury (Luo et al, 2019). The liver Igf1 specific knockout experiment showed that the appropriate dose of IGF‐1 supplementation significantly protects the mouse livers during the ALI process and promote the regeneration of the mouse livers, and the level of IGF‐1 has a significant correlation with the level of liver damage (Mirpuri et al, 2002; Morales‐Garza et al, 2017). Our results confirm that knockdown of Mof in the liver stimulates liver cell proliferation by activating the IGF‐1 signaling pathway, reduces liver function damage caused by CCl 4 , and promote liver regeneration.…”