Dataset Information

Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice.

ABSTRACT: Lipin-1 is a Mg²⁺-dependent phosphatidic acid phosphohydrolase involved in the generation of diacylglycerol during synthesis of phospholipids and triglycerides. Ethanol-mediated inhibitory effects on adipose-specific lipin-1 expression were associated with experimental steatohepatitis in rodents. In the present study, using an adipose-specific lipin-1 overexpression transgenic (Lpin1-Tg) mouse model, we tested a hypothesis that adipose-specific lipin-1 overexpression in mice might dampen ethanol-induced liver damage. Experimental alcoholic steatohepatitis was induced by pair-feeding ethanol to Lpin1-Tg and wild-type (WT) mice using the chronic-plus-binge ethanol feeding protocol. Unexpectedly, following the chronic-plus-binge ethanol challenge, Lpin1-Tg mice exhibited much more pronounced steatosis, exacerbated inflammation, augmented elevation of serum liver enzymes, hepatobiliary damage, and fibrogenic responses compared with the WT mice. Mechanistically, overexpression of adipose lipin-1 in mice facilitated the onset of hepatic ferroptosis, which is an iron-dependent form of cell death, and subsequently induced ferroptotic liver damage in mice under ethanol exposure. Concurrently, adipose lipin-1 overexpression induced defective adiponectin signaling pathways in ethanol-fed mice. Conclusion: We identified ferroptosis as a mechanism in mediating the detrimental effects of adipose-specific lipin-1 overexpression in mice under chronic-plus-binge ethanol exposure. Our present study sheds light on potential therapeutic approaches for the prevention and treatment of human alcoholic steatohepatitis.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC6492478 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice.

Zhou Zhou Z Ye Ting Jie TJ Bonavita Gregory G Daniels Michael M Kainrad Noah N Jogasuria Alvin A You Min M

Hepatology communications 20190312 5

Lipin-1 is a Mg<sup>2+</sup>-dependent phosphatidic acid phosphohydrolase involved in the generation of diacylglycerol during synthesis of phospholipids and triglycerides. Ethanol-mediated inhibitory effects on adipose-specific lipin-1 expression were associated with experimental steatohepatitis in rodents. In the present study, using an adipose-specific lipin-1 overexpression transgenic (<i>Lpin1</i>-Tg) mouse model, we tested a hypothesis that adipose-specific lipin-1 overexpression in mice mi ...[more]

PMID: 31061954

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Project description:The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for fatty acid (FA) uptake and is abundantly expressed in many metabolically active tissues. In the liver, CD36 is known to contribute to the progression of non-alcoholic fatty liver disease and to the more severe non-alcoholic steatohepatitis, by promoting triglyceride accumulation and subsequent lipid-induced endoplasmic reticulum (ER) stress. Given the recent discovery that the hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks CD36 expression, we sought to investigate the role of PCSK9 in liver fat accumulation and injury in response to saturated FAs and in a mouse model of diet-induced hepatic steatosis. Methods:In this study, we investigated the role of PCSK9 on the uptake and accumulation of FAs, as well as FA-induced toxicity, in a variety of cultured hepatocytes. Diet-induced hepatic steatosis and liver injury were also assessed in Pcsk9 -/- mice. Results:Our results indicate that PCSK9 deficiency in cultured hepatocytes increased the uptake and accumulation of saturated and unsaturated FAs. In the presence of saturated FAs, PCSK9 also protected cultured hepatocytes from ER stress and cytotoxicity. In line with these findings, a metabolic challenge using a high-fat diet caused severe hepatic steatosis, ER stress inflammation and fibrosis in the livers of Pcsk9 -/- mice compared to controls. Given that inhibition of CD36 ablated the observed accumulation of lipid in vitro and in vivo, our findings also highlight CD36 as a strong contributor to steatosis and liver injury in the context of PCSK9 deficiency. Conclusions:Collectively, our findings demonstrate that PCSK9 regulates hepatic triglyceride content in a manner dependent on CD36. In the presence of excess dietary fats, PCSK9 can also protect against hepatic steatosis and liver injury. Lay summary:The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein known to reduce the abundance of receptors on the surface of liver cells charged with the task of lipid uptake from the circulation. Although PCSK9 deficiency is known to cause lipid accumulation in mice and in cultured cells, the toxicological implications of this observation have not yet been reported. In this study, we demonstrate that PCSK9 can protect against cytotoxicity in cultured liver cells treated with a saturated fatty acid and we also show that Pcsk9 knockout mice develop increased liver injury in response to a high-fat diet.

Project description:Background & aimsNon-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement.MethodsAdult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI.ResultsTreatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively).ConclusionsIn adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF.Clinical trial numberNCT01265498.Impact and implicationsAlthough central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.

Dataset Information

Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice.

Publications

Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice.

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