Herp knockout protects against nonalcoholic fatty liver disease in mice on a high fat diet

Abstract

This study aims to discover the role of Homocysteine-induced ER protein (Herp) deficiency in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). After 8 weeks of feeding with normal-fat diet (NFD) or HFD, WT (wild type) and Herp −/− mice were measured for the body weight, liver weight and serum biochemical parameters. HE, Oil Red O, and Sirius red stainings were used to evaluate the histopathological changes of liver tissues. QRT-PCR, Western blotting and Immunohistochemistry were employed to detect the mRNA and protein expression. TUNEL staining was used to observe the hepatocyte apoptosis. Herp knockout reduced the liver/body weight ratio of mice fed with HFD with the decreased serum levels of TG, TC, HDL, LDL, GGT, Hcy, ALT, and AST. Besides, WT mice fed with HFD presented obvious steatosis, inflammation and hepatocytes ballooning, which was relieved in Herp −/− mice. HFD-induce NFALD mice demonstrated increased Oil Red, Sirius red, and α-SMA staining than NFD-induced mice, but mice in the Herp −/− + HFD group was lower than the WT + HFD group. HFD-induce NFALD mice showed upregulated expression of Grp78, Chop, and Atf4 in liver tissues when compared with NFD fed mice. However, regarding to the mice fed with HFD, Herp deficiency decrease in the expression of Grp78, Chop, and Atf4 in liver tissues with the reduced hepatocyte apoptosis. Herp was highly expressed in HFD-induced NAFLD mice. Herp knockout improved liver function and histopathological conditions with the decreased hepatocyte apoptosis and endoplasmic reticulum stress (ERS) of HFDinduce NFALD mice.

Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress

“…Numerous studies have shown that HERP is implicated in diverse cellular processes including ERAD [12] , [19] , [28] , metabolic regulation [16] , Ca 2+ homeostasis [14] , cell proliferation [17] , [30] , cell apoptosis [17] , and ferroptosis [18] . However, further functions and the exact mechanisms by which HERP carries out its biological functions are still unknown.…”

“…HERP is strongly upregulated by the unfolded protein response, which has been closely related to the pathogenesis of Parkinson’s disease, type 2 diabetes, and neurodegeneration [13] , [14] , [15] . According to a previous report, HERP may play a role in nonalcoholic fatty liver disease (NAFLD) [16] , which indicates that HERP could influence metabolism. Emerging data suggests that HERP mediates the regulation of liver cancer cell survival, inhibiting cell apoptosis and ferroptosis by different signaling pathways [17] , [18] .…”

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver

“…Tissues were paraffin embedded and sectioned at a thickness of 5 μ m. Masson staining and wheat germ agglutinin (WGA) staining were performed to assess cardiac fibrosis and hypertrophy, respectively, as described previously [ 6 ]. Haematoxylin-eosin (H&E) and Oil Red staining were performed to assess structural changes and lipid accumulation in the liver, respectively, as described previously [ 22 ]. The fluorescence of WGA was imaged using an inverted confocal microscope (Zeiss LSM 800).…”