Deletion of KLF10 Leads to Stress-Induced Liver Fibrosis upon High Sucrose Feeding

Abstract

Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and Klf10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. Klf10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed Klf10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Klf10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism

“…The link between altered metabolic homeostasis and inflammation is well established (Saltiel and Olefsky, 2017). Recent studies have highlighted the role of KLF10 in regulating inflammation (Huang et al, 2016;Wara et al, 2020;Yang et al, 2020) and in attenuating liver injury in mice with NASH ad fibrosis (Lee et al, 2020). In this study, we found apoptosis and inflammation related processes as gene sets that gain circadian coordination in unchallenged hepKO mice.…”

KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7

“…Besides, KLF10 expression could be induced by carbohydrate response element‐binding protein (ChREBP) upon glucose stimulation in mouse hepatocytes (Iizuka et al , 2011). KLF10 knockout mice exhibited significant hepatic steatosis, inflammation, and liver injury upon high sucrose diet feeding (Lee et al , 2020). T cell‐specific KLF10 knockout mice were susceptible to diet‐induced obesity, insulin resistance, and fatty liver (Wara et al , 2020).…”

Current Options and Future Directions for NAFLD and NASH Treatment

“…Krüppel-like factors ( KLFs ) are transcription factors that play pivotal roles in diseases. For example, KLF10 -deficient mice on a high-sucrose diet promoted the progression of hepatic steatosis, inflammation, and fibrosis compared to wild-type mice [ 24 ]. Another study showed that KLF15 can activate twist-related protein 2 ( TWIST2 ) to ameliorate liver steatosis and inflammation by modulating nuclear factor ( NF ) -κB or sterol regulatory element-binding protein 1c ( SREBP1c )-fibroblast growth factor 21 ( FGF21 ) signaling pathways [ 25 ].…”

“…In addition, there are some other targets for NAFLD and NASH treatments, such as G protein-coupled receptors ( GPCRs ) [ 142 ], estrogen-related receptor alpha ( ERRα ) [ 143 ], bone morphogenetic proteins ( BMPs ) [ 144 ], and KLFs [ 24 , 145 ]. The treatment options for NAFLD/NASH are summarized in the graphic picture ( Figure 2 ).…”