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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-? (TGF-?) 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-?-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.

SUBMITTER: Lee J

PROVIDER: S-EPMC7794950 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Lee Junghoon J Oh Ah-Reum AR Lee Hui-Young HY Moon Young-Ah YA Lee Ho-Jae HJ Cha Ji-Young JY

International journal of molecular sciences 20201230 1

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 ...[more]

PMID: 33396939

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Project description:BackgroundThe metabolic syndrome (MetS) is correlated with disorders of the reproductive system, such as the polycystic ovary syndrome (PCOS). While consumption of a diet rich in carbohydrates is linked to the development of MetS, it is still unclear if this diet leads to ovarian dysfunction and PCOS.ObjectivesWe investigated the influence of a high-sucrose diet (HSD) on the ovarian milieu of Wistar rats and studied the correlation between high consumption of sugary drinks and the prevalence of PCOS in women.MethodsWistar rats were given a standard laboratory diet (CTR, 10% sucrose, n = 8) or HSD (HSD, 25% sucrose, n = 8) from postnatal day 21 to 120. Animals were evaluated weekly to calculate food intake, feed efficiency and weight gain. Both onset of puberty and estrous cycle were monitored. Metabolic serum biochemistry, organ morphometry and ovarian histology were performed upon euthanasia. In parallel, a fixed-effects multiple linear regression analysis was performed using data from Brazilian states (459 state-year observations) to test the correlation between the consumption of sugar-sweetened beverages (surrogate for HSD intake) and the prevalence of PCOS (surrogate for ovarian dysfunction).ResultsHSD animals showed increased adipose tissue accumulation, hyperglycaemia and insulin resistance when compared to CTR. Interestingly HSD rats also entered puberty earlier than CTR. Moreover, ovaries from HSD animals had an increased number of atretic antral follicles and cystic follicles, which were correlated with the hypertrophy of periovarian adipocytes. Finally, there was a positive correlation between the intake of sugary drinks and prevalence of PCOS in women of reproductive age.ConclusionsHSD ingestion leads to ovarian dysfunction in rats and could be correlated with PCOS in women, suggesting these alterations could lead to public health issues. Therefore, we reinforce the deleterious impact of HSD to the ovarian system and suggest that the reduction of added sugars intake could be beneficial to ovarian health.

Project description:High-carbohydrate diets contribute to the development of liver stress and fatty liver disease. While saturated fatty acids are known to induce liver stress, the role of monounsaturated fatty acids (MUFA), synthesized by the stearoyl-CoA desaturase (SCD) family of enzymes, in regulation of liver function during lipogenic dietary conditions remains largely unknown. The major products of SCD-catalyzed reactions are oleate (18:1n-9) and palmitoleate (16:1n-7).We generated mouse models with restricted exogenous MUFA supply and reduced endogenous MUFA synthesis, in which SCD1 global knockout (GKO) or liver-specific knockout (LKO) mice were fed a lipogenic high-sucrose very low-fat (HSVLF) or high-carbohydrate (HC) diet. In a gain-of-function context, we introduced liver-specific expression of either human SCD5, which synthesizes 18:1n-9, or mouse Scd3, which synthesizes 16:1n-7, into SCD1 GKO mice and fed the HSVLF diet.Lipogenic high-carbohydrate diets induced hepatic endoplasmic reticulum (ER) stress and inflammation in SCD1 GKO and LKO mice. Dietary supplementation with 18:1n-9, but not 18:0, prevented the HSVLF diet-induced hepatic ER stress and inflammation in SCD1 LKO mice, while hepatic SCD5, but not Scd3, expression reduced the ER stress and inflammation in GKO mice. Additional experiments revealed liver-specific deletion of the transcriptional coactivator PGC-1? reduced hepatic inflammatory and ER stress response gene expression in SCD1 LKO mice.Our results demonstrate an indispensable role of hepatic oleate in protection against lipogenic diet-induced hepatic injury, and PGC-1? potentiates the ER stress response under conditions of restricted dietary oleate coupled to reduced capacity of endogenous hepatic oleate synthesis.Susceptibility to metabolic dysfunction is influenced by genetic and environmental factors. In this study we show that modulation of two genes regulates the liver response, including ER stress and inflammation, to a high-carbohydrate low-fat diet. We reveal that hepatic availability of oleate, a monounsaturated fatty acid, is important for maintenance of liver health.

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

Publications

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

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