Hypoxia inducible factor‐1 promotes liver fibrosis in nonalcoholic fatty liver disease by activating PTEN/p65 signaling pathway

Abstract

Obesity is a major contributor to the development of steatohepatitis and fibrosis from nonalcoholic fatty liver disease (NAFLD). Hypoxia aggravates progression of NAFLD. In mice on high‐fat diet (HFD), hepatic steatosis leads to liver tissue hypoxia, evidenced by accumulation of hypoxia inducible factor‐1‐alpha (HIF‐1α), which is a central regulator of the global response to hypoxia. Hepatocyte cell signaling is an important factor in hepatic fibrogenesis. We here hypothesize that HIF‐1α knockout in hepatocyte may protect against liver fibrosis. We first found that HFD led to 80% more hepatic collagen deposition than Hif1a−/−hep mice, which was confirmed by a‐SMA staining of liver tissue. Body weight and liver weight were similar between groups. We then found the increasing HIF1a expression and decreasing PTEN expression in the mice on HFD and in PA‐treated HepG2 cells. Finally, we found that HIF1 mediated PTEN/nfkb‐p65 pathway plays an important role in the development of NAFLD to liver fibrosis. Collectively, these results identify a novel HIF1a/PTEN/NF‐κ Bp65 signaling pathway in NAFLD, which could be targeted for the therapy.

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…Cxcl1 , Cxcl11 , Hif1a , Col4a1 , and Fn1 were unexpectedly elevated in the liver of MPF versus EF mice, suggesting that SFB within the complex commensal gut microbiota leads to proinflammatory innate immune response effects in the liver. Astonishingly, these findings are in line with seminal reports demonstrating that CXCL1, CXCL11, HIF1A, COL4A1, and FN1 are implicated in liver fibrosis …”

“…Interestingly, CXCL11 has also been shown to endorse T H 1 cell proinflammatory cytokine production and facilitate T H 17 cell development in an experimental colitis model . Hypoxia inducible factor 1 ( Hif1a ), collagen type IV ( Col4a1 ), and fibronectin ( Fn1 ) are profibrotic factors that promote liver fibrosis . Considering that SFB colonization within a complex gut microbiota increased serum IL17A levels (Fig.…”

“…Astonishingly, these findings are in line with seminal reports demonstrating that CXCL1, CXCL11, HIF1A, COL4A1, and FN1 are implicated in liver fibrosis. (66,(73)(74)(75)(76)(77)(78)(109)(110)(111) The liver is exposed to commensal gut microbiota-derived ligands/metabolites through the portal venous circulation. (112)(113)(114) DCs are critical in presenting antigens to promote T-cell activation in liver-draining lymph nodes.…”

“…(72) Hypoxia inducible factor 1 (Hif1a), collagen type IV (Col4a1), and fibronectin (Fn1) are profibrotic factors that promote liver fibrosis. (73)(74)(75)(76)(77)(78) Considering that SFB colonization within a complex gut microbiota increased serum IL17A levels (Fig. 3F), gene expression studies were carried out in livers from EF and MPF mice to assess chemokines and profibrotic factors implicated in proinflammatory hepatic immune response states (Fig.…”

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

“…Hypoxia-inducible factor 1 alpha (HIF-1α) is known to be a key regulator of a tissue's response to hypoxia [26] and plays a role in obesity-induced metabolic syndrome. It has been shown that HFD leads to gradual increase in HIF-1α and associated pathological changes in the liver [27,28]. However, the role of HIF-1α in the retina of WD-fed mice is not known.…”