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Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT^+/+) and hepatocyte-specific AGT-deficient mice (hepAGT^-/-) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT^+/+ mice, Western diet-fed hepAGT^-/- mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT^-/- mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT^-/- mice. Furthermore, serum derived from hepAGT^+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT^+/+ mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT^-/- mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

SUBMITTER: Tao XR

PROVIDER: S-EPMC6889717 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

Tao Xin-Ran XR Rong Jia-Bing JB Lu Hong S HS Daugherty Alan A Shi Peng P Ke Chang-Le CL Zhang Zhao-Cai ZC Xu Yin-Chuan YC Wang Jian-An JA

Journal of lipid research 20191011 12

Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT<sup>+/+</sup>) and hepatocyte-specific AGT-deficient mice (hepAGT<sup>-/-</sup>) were fed a West ...[more]

PMID: 31604805

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Project description:ObjectivePARKIN is an E3 ubiquitin ligase that regulates mitochondrial quality control through a process called mitophagy. Recent human and rodent studies suggest that loss of hepatic mitophagy may occur during the pathogenesis of obesity-associated fatty liver and contribute to changes in mitochondrial metabolism associated with this disease. Whole-body Prkn knockout mice are paradoxically protected against diet-induced hepatic steatosis; however, liver-specific effects of Prkn deficiency cannot be discerned in this model due to pleotropic effects of germline Prkn deletion on energy balance and subsequent protection against diet-induced obesity. We therefore generated the first liver-specific Prkn knockout mouse strain (LKO) to directly address the role of hepatic Prkn.MethodsLittermate control (WT) and LKO mice were fed regular chow (RC) or high-fat diet (HFD) and changes in body weight and composition were measured over time. Liver mitochondrial content was assessed using multiple, complementary techniques, and mitochondrial respiratory capacity was assessed using Oroboros O2K platform. Liver fat was measured biochemically and assessed histologically, while global changes in hepatic gene expression were measured by RNA-seq. Whole-body and tissue-specific insulin resistance were assessed by hyperinsulinemic-euglycemic clamp with isotopic tracers.ResultsLiver-specific deletion of Prkn had no effect on body weight or adiposity during RC or HFD feeding; however, hepatic steatosis was increased by 45% in HFD-fed LKO compared with WT mice (P < 0.05). While there were no differences in mitochondrial content between genotypes on either diet, mitochondrial respiratory capacity and efficiency in the liver were significantly reduced in LKO mice. Gene enrichment analyses from liver RNA-seq results suggested significant changes in pathways related to lipid metabolism and fibrosis in HFD-fed Prkn knockout mice. Finally, whole-body insulin sensitivity was reduced by 35% in HFD-fed LKO mice (P < 0.05), which was primarily due to increased hepatic insulin resistance (60% of whole-body effect; P = 0.11).ConclusionsThese data demonstrate that PARKIN contributes to mitochondrial homeostasis in the liver and plays a protective role against the pathogenesis of hepatic steatosis and insulin resistance.

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Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

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Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

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