Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet

SIMPLE SUMMARY: The nuclear protein Krüppel-like factor 9 (KLF9) suppresses development of cancers in multiple tissues including the liver. However, a mechanistic basis for how KLF9 decreases cancer initiation/development has not been elucidated. Here, we used a mouse model in which the Klf9 gene was ablated and placed wild-type and mutant animals of both sexes on a high-fat, obesogenic diet. We then examined how the presence or absence of KLF9 affected adiposity, as well as indices of liver oxidative stress and inflammation, and systemic oxidative stress. Results demonstrate that KLF9 is a suppressor of liver oxidative stress and inflammation which may underlie its tumor suppressive actions in liver and other tissues. ABSTRACT: Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female Klf9(+/+) (wild type, WT) and Klf9(−/−) (knockout, KO) mice were fed HFD (beginning at age 35 days) for 12 weeks, after which liver and adipose tissues were obtained, and serum adiponectin and leptin levels, liver fat content, and markers of oxidative stress evaluated. Klf9(−/−) mice of either sex did not exhibit significant alterations in weight gain, adipocyte size, adipokine levels, or liver fat content when compared to WT counterparts. However, Klf9(−/−) mice of both sexes had increased liver weight/size (hepatomegaly). This was accompanied by increased hepatic oxidative stress as indicated by decreased GSH/GSSG ratio and increased homocysteine, 3-nitrotyrosine, 3-chlorotyrosine, and 4HNE content. Decreased GSH to GSSG ratio and a trend toward increased homocysteine levels were observed in the corresponding Klf9(−/−) mouse serum. Gene expression analysis showed a heightened pro-inflammatory state in livers from Klf9(−/−) mice. KLF9 suppresses hepatic oxidative stress and inflammation, thus identifying potential mechanisms for KLF9 suppression of HCC and perhaps cancers of other tissues.