Lipocalin‐2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high‐fat diet–fed Ob/Ob mice

Abstract

Background and Aims: In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.Approach and Results: Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA

Hyponatremia-related liver steatofibrosis and impaired spermatogenesis: evidence from a mouse model of the syndrome of inappropriate antidiuresis

“…5 a, b). To identify the nature of cells expressing HMOX 1 in the liver of hyponatremic animals, serial liver sections were subjected to immunohistochemistry analysis for F480, a marker of activated Kupffer cells in the liver [ 25 , 26 ], and αSMA, a marker of myo-fibroblast formation, as previously mentioned, which is expressed by activated Hepatic Stellate Cells (HSC) [ 27 ]. Very low (F480) or no immuno-positivity (α-SMA) were found in the liver of normonatremic mice, whereas evident positive staining was observed for both markers in liver sections of hyponatrenic mice (Fig.…”

Electroacupuncture regulates the cross-talk between Islets and Peripancreatic Adipose tissue to combat obesity combined with insulin resistance

“…Our study also demonstrate a similar phenomenon, which gives us con dence that rats can be used to simulate obese patients with insulin resistance. Leptin resistance and insulin resistance are two disorders that can have a synergistic effect on energy balance and glucose and lipid metabolism [42]. Dysfunctional adipose tissue is closely associated with the development of T2DM; however, the mechanisms by which insulin resistance develops is poorly understood [43].…”

An update on animal models of liver fibrosis

“…However, liver inflammation and fibrosis in genetically defective ob/ob , db/db mice, fa/ fa rats, or partially transgenic mice models are mild and can induce varying degrees of inflammation and liver fibrosis when combined with dietary measures (feeding MCD or HFD diet) ( 159 ). Kim et al ( 160 ) fed ob/ob mice to a HFD for 20 weeks to establish an animal model of NASH with fibrosis. Treatment of ob/ob mice fed a long-term high-fat diet resulted in significant weight loss, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance >1 year ( 161 ).…”