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Liver-specific ROR? deletion does not affect the metabolic susceptibility to western style diet feeding.

ABSTRACT: OBJECTIVES:The nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (ROR?) as an important nuclear receptor involved in several biological processes. ROR? full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic ROR? by generating mice with liver-specific ROR? deletion to elucidate the role of this nuclear receptor on host metabolism. METHODS:8 week-old mice with liver-specific ROR? deletion and littermate controls were fed either chow or western-style diets (40% fat, 40% carbohydrate) for 12 weeks. Metabolic phenotyping was performed at the end of the dietary intervention. RESULTS:Here, we show that hepatic ROR? deletion does not affect the metabolic susceptibility to either chow or western-style diet in terms of glucose metabolism and adiposity. CONCLUSIONS:Our data indicate that liver deletion of ROR? does not have a pivotal role in the regulation of hepatic glucose and lipid metabolism on chow or western-style diet.

SUBMITTER: Molinaro A

PROVIDER: S-EPMC6479759 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding.

Molinaro Antonio A Caesar Robert R L'homme Laurent L Koh Ara A Ståhlman Marcus M Staels Bart B Bäckhed Fredrik F

Molecular metabolism 20190309

<h4>Objectives</h4>The nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we ...[more]

PMID: 30904385

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Project description:Metabolic-associated steatohepatitis (MASH), the inflammatory stage of MASLD, will soon be one of the primary causes of liver-related complications, including advanced fibrosis and hepatocellular carcinoma. Its steady increase in both the US and the global population is devastating. Between the two genders, more women are suffering from MASH compared to the man due to estrogen deficiency caused by polycystic ovary syndrome or menopause. Our published data shows a clear positive association between the progression of liver disease and the expression of novel hexokinase HKDC1 in the liver. Targeting HKDC1, which is highly expressed in pathological hepatocytes (in MASH) but negligible in normal hepatocytes, represents a highly selective approach. Therefore, we hypothesized that liver-specific deletion of HKDC1 will protect against diet-induced obesity and the progression of MASH to fibrosis. We used an early-onset liver knockout (LKO) of HKDC1 by crossing HKDC1 floxed mice with Albumin Cre mice to test our hypothesis. We fed the Western Diet to HKDC1LKO female mice along with HKDC1 floxed mice (HKDC1fl/fl; as Controls) for 28 weeks. Our data shows that HKDC1 deletion significantly decreases body weight and fat mass compared to HKDC1fl/fl mice with no changes in food intake and energy expenditure. Knockout mice have better glucose tolerance and lower fasting glucose levels than HKDC1fl/fl mice. Our data also shows that the knockout group has smaller livers, healthier liver parameters, less steatosis, and lower NAS and fibrosis scores. Furthermore, HKDC1 knockout alters hepatic gene expression, and we found significantly low proinflammatory and profibrogenic gene expression in the LKO mice. Although we did not see any changes in triglyceride levels, there was a significant reduction of serum cholesterol concomitant with enhanced expression of cholesterol metabolism genes in the knockout group. Our data suggest a promising protective role of HKDC1 deletion against diet-induced obesity and MASH mice.

Dataset Information

Liver-specific ROR? deletion does not affect the metabolic susceptibility to western style diet feeding.

Publications

Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding.

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