Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability

Abstract

Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.

Insulin‐like growth factor binding protein 7 accelerates hepatic steatosis and insulin resistance in non‐alcoholic fatty liver disease

“…Elevated expression of SREBP‐1c leads to the transcriptional activation of downstream pivotal lipogenic rate‐limiting enzymes involved in DNL, including acetyl‐CoA carboxylase (ACC1), fatty acid synthase (FASN), ATP‐citrate lyase (ACL) and stearoyl‐CoA desaturase‐1 (SCD1) . Previous studies have strengthened the observation of enhanced SREBP‐1c expression in NAFLD patients and the increase in hepatic TG levels in transgenic mice with SREBP‐1c overexpression, while SREBP‐1c ablation has been shown to reduce transcription of lipogenic enzymes in SREBP‐1c knockout mice . Our study suggested that IGFBP7 knockdown could inhibit DNL synthesis in HFD‐treated mice by repressing the transcriptional activation of SREBP‐1c, FASN, SCD1 and ACC1, which was further confirmed by in vitro results.…”

The Effectiveness of Combined Drug Delivery Systems

“…The end conjugate develops a spherical nanoparticle that has up to 8 active drugs. In addition to camptothecin, disulfide bonding is used to crosslink with the nanoparticles and this act as a nano drug delivery system [14][15][16][17] . In some instances, paclitaxel and camptothecin are conjugated to develop a beta sheet forming multiple compounds and peptides.…”

Peptide Conjugated Lipid Nanoparticles for Anti-Cancer Drug Delivery

“…Sun et al analyzed the effects of using peptide ligand structures for Doxorubicin DOX drug delivery in the case of breast cancer treatment and lymphoma treatment [8][9][10][11][12][13][14] . Traditionally, although DOX was effective for breast cancer treatment, the cardiotoxicity concerns necessitated the research into finding more suitable alternatives for drug delivery.…”

“…Thus, in the context of cancer, anti-angiogenesis refers to the inhibition of the formation of those new vessels that make the cancer cells thrive. The researchers used a drug delivery system DDS where the nanoparticles conjugated with the peptides [6][7][8][9][10][11][12][13] . The size of the conjugated nanoparticles made it easier for those particles to be assimilated and internalized within the human umbilical vein and expected antiangiogenic activity occurred.…”