Insulin-Like Growth Factor (IGF) System in Liver Diseases

Abstract

Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R). The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth), and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma). Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

Evaluation of the Effect Derived from Silybin with Vitamin D and Vitamin E Administration on Clinical, Metabolic, Endothelial Dysfunction, Oxidative Stress Parameters, and Serological Worsening Markers in Nonalcoholic Fatty Liver Disease Patients

“…Oxidative Medicine and Cellular Longevity to a population of hepatologically healthy subjects (with only reflux disease not being treated) for several of the parameters evaluated. Specifically, NAFLD patients demonstrated greater BMI, body weight, insulin, HOMA-IR, total cholesterol, triglycerides, CRP, TNF-α, EGFR, CD-44, IL-18, IGF-II, IL-22, TGF-β, MMP-2, Endocan, HMGB-1, and TBARS, with the evidence, moreover, of lower average levels of vitamin D. This pathological picture fully reflects the data present in the scientific literature showing how patients affected by NAFLD are more exposed to oxidative stress, systemic inflammation, and endothelial dysfunction and have a higher blood level of inflammatory cytokines and fibrosis markers compared to healthy subjects, thus being more predisposed to all the pathologies supported by these harmful factors [47][48][49][50].…”

“…Furthermore, it would be able to act on hepatic stellate cells by inhibiting the extracellular signal-related kinase (ERK) activity, MAP/ERK kinase (MEK), and Raf phosphorylation, reducing the migration of leukocytes to the site of inflammation and reducing TGF-β-induced synthesis of type I procollagen as well as MMP-2 secretion [53]. These biological activities are responsible for controlling the inflammatory cascade, the deposition of fat accumulation in the hepatocytes, and the reduction of hepatic and extrahepatic deposition of fibrotic tissue [47][48][49][50]. An interesting point is represented by the fact that the improvement of the markers of disease worsening assessed is maintained well beyond the end of the treatment period.…”

A Microphysiological System for Studying Nonalcoholic Steatohepatitis

“…The co-cultures also exhibited a range of transcriptomic changes as compared with the PHH-only steatosis model. Gene-expression changes associated with NAFLD/NASH development were observed, including increased expression of genes associated with insulin resistance (e.g., IGF1, IGFB1 (39) ), glucose metabolism (e.g., G6PD, (40) PDK4 (41) ), and lipid metabolism (e.g., FABP5, (42) LPL (43) ).…”

Laboratory investigations in the diagnosis and follow-up of GH-related disorders

“…Lower IGF-I has been reported in the majority of cases of chronic kidney disease and uremia, but most importantly, in these conditions its bioactivity is reduced, perhaps due to impaired elimination of binding proteins (59,60). In liver diseases, depending of the severity of the disease, IGF-I synthesis may be impaired, resulting in lower IGF-I concentrations (61). Furthermore, reduced expression of GHR and GH resistance can occur, a mechanism which also has been suggested to explain the reduced IGF-I concentrations seen in acute critical illness and systemic inflammation (62,63).…”