Mechanistic insights into the effects of SREBP1c on hepatic stellate cell and liver fibrosis

Abstract

Sterol regulatory element‐binding protein 1c (SREBP1c) plays key roles in maintenance of hepatic stellate cell (HSC) quiescence. The present researches investigated the mechanisms underlying the effects of SREBP1c on HSCs and liver fibrogenesis by HSC‐targeted overexpression of the active SREBP1c using adenovirus in vitro and in vivo. Results demonstrated that SREBP1c exerted inhibitory effects on TAA‐induced liver fibrosis. SREBP1c down‐regulated TGFβ1 level in liver, reduced the receptors for TGFβ1 and PDGFβ, and interrupted the signalling pathways of Smad3 and Akt1/2/3 but not ERK1/2 in HSCs. SREBP1c also led to the decreases in the protein levels of the bromodomain‐containing chromatin‐modifying factor bromodomain protein 4, methionine adenosyltransferase 2B (MAT2B) and TIMP1 in HSCs. In vivo activated HSCs did not express cyclin D1 and cyclin E1 but SREBP1c down‐regulated both cyclins in vitro. SREBP1c elevated PPARγ and MMP1 protein levels in the model of liver fibrosis. The effect of SREBP1c on MAT2B expression was associated with its binding to MAT2B1 promoter. Taken together, the mechanisms underlying the effects of SREBP1c on HSC activation and liver fibrosis were involved in its influences on TGFβ1 level, the receptors for TGFβ1 and PDGFβ and their downstream signalling, and the molecules for epigenetic regulation of genes.

PNPLA3 downregulation exacerbates the fibrotic response in human hepatic stellate cells

“…Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in the de novo synthesis of lipids and its inhibition in hepatocytes increases the expression of SREBP-1c, the transcriptional regulator of PNPLA3 [ 10 , 21 ]. Because ACCi leads to inactivation of stellate cells [ 22 ] and upregulation of SREBP-1c in HSCs has been shown to inactivate fibrotic stellate cells [ 23 ] we evaluated whether ACC inhibition modulates PNPLA3 in primary human HSC [ 22 , 23 ]. Human HSCs were treated with ACCi or with a small molecule inhibitor of ALK5 as a positive control in the presence of TGF-β.…”

“…This last report is consistent with our data showing use of an ACC inhibitor in human HSCs enhanced the expression of PNPLA3 and was associated with inhibition of HSC activation. Together, these data suggest that expression of PNPLA3 in HSCs could be a protective mechanism that restrains activation [ 23 ].…”

Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism

“…This property can protect HSCs from stress-induced injury and prevent their premature aging and exhaustion during long-term hematopoietic output ( Takubo et al., 2010 ; Wang et al., 2021 ). Previous studies have shown that Srebf1c maintains the quiescence of hepatic satellite cells, but promotes the proliferation of pancreatic β cells ( Lee et al., 2019 ; Su et al., 2020 ). In our study, we observed that the deletion of Srebf1c significantly impaired HSC quiescence, resulting in increased sensitivity to 5-FU and irradiation and decreased long-term repopulation capacity.…”

Protective Mechanism of Nostoc sphaeroides Kütz. Polysaccharide on Liver Fibrosis by HFD-Induced Liver Fat Synthesis and Oxidative Stress

“…Two important factors of fat accumulation in the liver are blocked free fatty acid transport and abnormal increase of fat synthesis, and the genes SREBP-1c and FAS of fat synthesis play a key role in steatosis [ 35 , 36 ]. It has been reported that SREBP-1c can regulate FAS expression and lead to TG synthesis, and the mechanisms underlying the effects of SREBP-1c on hepatic stellate cell activation and liver fibrosis were involved in its influences on the receptors for TGF-β1 and PDGF- β and their downstream signaling, and the molecules for epigenetic regulation of genes [ 37 ]. The high-fat diet has been confirmed to cause TG and TC accumulation by increasing SREBP-1c and FAS expression [ 38 , 39 ].…”