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Ileum single cells expression in mice lacking Pgc1α in the intestine in response to western diet feeding.

ABSTRACT: To generate iPGC1α-/- mice, PGC1αfl/fl mice were intercrossed with Vil1-Cre mice to obatin Vil1-CreTg/-PGC1αfl/- mice. These mice were then backcrossed with PGC1αfl/fl mice to restore homozygosity for the iPGC1α floxed allele. Male Vil1-CreTg/-PGC1αfl/fl mice were bred to PGC1αfl/fl to produce the mice used in the study. PGC1αfl/fl (iPGC1afl/fl) littermates were used as controls.

ORGANISM(S): Mus musculus

PROVIDER: GSE227610 | GEO | 2023/11/02

REPOSITORIES: GEO

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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.

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Ileum single cells expression in mice lacking Pgc1α in the intestine in response to western diet feeding.

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