Abstract
Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)–associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity.
Highlights
Proteins are the main workforces of a cell, and protein synthesis is highly controlled according to cellular needs
Our analysis demonstrated for the first time that protein synthesis is progressively suppressed in the obese liver and that the overall translatome profile of obese liver markedly resembles that of fasting lean mice, in mitochondrial function and bile metabolism
We examined the physiological impact of some of these alterations and concluded that aberrant bile acid metabolism in the obese liver represents a novel mechanism contributing to hyperglycemia and continuous weight gain
Summary
Proteins are the main workforces of a cell, and protein synthesis is highly controlled according to cellular needs. Cells modulate protein synthesis in response to hormonal cues, nutrient availability and episodes of intracellular stress. Nutrients, Lbranched amino acids, activate protein synthesis through the mammalian target of rapamycin pathway (mTOR) and its downstream effectors such as ribosomal protein S6 kinase (S6K1) and eukaryotic translation initiation factor 4 binding protein (eIF4BP1) [6,7,8,9,10]. Cells modulate the rate of protein synthesis in response to stresses invoked by energy depletion, virus infection, and dysfunctional protein folding, through AMP-dependent protein kinase (AMPK) and multiple eukaryotic translation initiation factor 2 alpha (eIF2a) kinases, such as the interferon-induced, double-stranded RNA-activated protein kinase (PKR) and the PKR-like endoplasmic reticulum kinase (PERK) [11,12,13,14]. Due to the fundamental role of protein synthesis in cellular function, mutations in the protein synthesis machinery and its regulatory pathways have been broadly implicated in many diseases [15]
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