Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice

Abstract

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

“…Hematopoietic-specific loss of CD36 was associated with reduced adipose tissue inflammation and improved adipose tissue insulin signaling but without improvements in systemic insulin sensitivity (342). An adipose tissue-specific deletion of HSL was associated with lipodystrophic phenotypes including reduced adiposity, adipose tissue dysfunction, and impaired insulin sensitivity demonstrating that TG lipolysis is essential for maintenance of whole-body metabolic regulation (521). This is consistent with observations of humans with HSL deletion mutations, which are associated with impaired glucose homeostasis, with a redistribution of adipose tissue to visceral depots, adipose tissue inflammation, and an increased risk for T2DM (12).…”

A Review of Non-Alcoholic Fatty Liver Disease in HIV-Infected Patients: The Next Big Thing?

“…HSL is present in all adipocytes and is able to hydrolyse stored triglycerides into free fatty acids (FFAs) [48]. In the case of IR, the suppression of HSL is diminished, resulting in an increased hydrolysis in peripheral adipose tissue and therefore an increase in delivery of FFAs to the liver [49]. In the liver, the FFAs undergo esterification into triglycerides contributing to the process of steatosis.…”

Regulatory roles of adiponectin receptor 1 and 2 in sheep preadipocytes during adipocyte differentiation

“…It is possible that AdipoR2 is predominantly expressed in the liver. HSL, a key neutral fat enzyme, expresses predominantly in adipose tissue, where it plays an important role in controlling lipid and energy metabolism (Xia et al 2017). HSL is regulated by various hormones, such as catecholamine, insulin and adrenaline (Nakatsuji et al 2010).…”