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Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

ABSTRACT: Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

PROVIDER: PRJNA701620 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13697458_1.fastq.gz	Fastqsanger.gz
	SRR13697458_2.fastq.gz	Fastqsanger.gz
	SRR13697459_1.fastq.gz	Fastqsanger.gz
	SRR13697459_2.fastq.gz	Fastqsanger.gz
	SRR13697460_1.fastq.gz	Fastqsanger.gz

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Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Project description:We report how human hepatocytes with PNPLA3 148I and 148M variants (rs738409) engrafted in the livers of chimeric mice respond to different durations of hypercaloric western style diet (WD). To determine how WD affected human and mouse gene expression we performed RNA-sequencing (RNA-seq) on livers from fasting mice.

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Induced Pluripotent Stem Cell Derived Liver Model for the Study of PNPLA3 Associated Non-Alcoholic Fatty Liver Disease

Project description:In order to identify molecular mechanisms associated with PNPLA3 associated non-alcoholic fatty liver disease, we ran RNA sequencing on human induced pluripotent stem cell-derived hepatocyte like cells that were homozygous for the wild type PNPLA3 allele, homozygous for the risk PNPLA3 allele (I148M), or had a complete knock-out of the PNPLA3 gene. The cells were then treated with either oleic acid or palmitic acid to induce a steatotic or a lipotoxic phenotype, respectively. The cells were treated with control medium or medium supplemented with 0.25 mM oleic acid or palmitic acid for 24 hours before samples were collected for RNA sequencing.

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Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice.

Project description:Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

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The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics

Project description:Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-drivencellular change.

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The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics

Project description:Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD to date. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.

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Hepatocyte FoxO1 depletion exacerbates hepatic inflammation in MASH

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A functional interaction between hepatic Estrogen Receptor-a and PNPLA3 p.I148M variant drives fatty liver diseases susceptibility in women

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