Background Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. Methods We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. Results A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was found to be associated with reduced levels of ALT (P=4.2×10−12) and AST (P=6.2×10−10). Among DiscovEHR study participants, this variant was found to be associated with a re...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1712191

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease

Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.

Triglyceride Metabolism in the Liver

Lipotoxicity drives the development of progressive hepatic inflammation and fibrosis in a subgroup of patients with nonalcoholic fatty liver disease (NAFLD), causing nonalcoholic steatohepatitis (NASH) and even progression to cirrhosis and hepatocellular carcinoma (HCC). While the underlying molecular mechanisms responsible for the development of inflammation and fibrosis that characterize progressive NASH remain unclear, emerging evidence now suggests that hepatic free cholesterol (FC) is a major lipotoxic molecule critical in the development of experimental and human NASH. In this review, we examine the effects of excess FC in hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs), and the subcellular mechanisms by which excess FC can induce cellular toxicity or proinflammatory and profibrotic effects in these cells.

The Role of Cholesterol in the Pathogenesis of NASH

Intracellular lipid droplets (LDs) are found in a wide variety of cell types and have been recognized as organelles with unique spherical structures. Although LDs are not stable lipid-depots, they are active sites of neutral lipid metabolism, and comprise neutral lipid or cholesterol cores surrounded by phospholipid monolayers containing specialized proteins. However, sizes and protein compositions vary between cell and tissue types. Proteins of the perilipin family have been associated with surfaces of LDs and all carry a conserved 11-mer repeat motif. Accumulating evidence indicates that all perilipins are involved in LD formation and that all play roles in LD function under differing conditions. In this brief review, we summarize current knowledge of the roles of perilipins and lipid metabolizing enzymes in a variety of mammalian cell types.

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Perilipins: a diversity of intracellular lipid droplet proteins

Lipid droplets are the universal cellular organelles for the transient or long-term storage of lipids. The number, size and composition of lipid droplets vary greatly within cells in a homogenous population as well as in different cell types. The variability of intracellular lipid-storage organelles reflects the diversification of lipid droplet composition and function. Lipid droplet diversification results, for example, in two cellular lipid droplet populations that are prone to diminish and grow, respectively. The aberrant accumulation or depletion of lipids are hallmarks or causes of various human pathologies. Thus, a better understanding of the origins of lipid droplet diversification is not only a fascinating cell biology question but also potentially serves to improve comprehension of pathologies that entail the accumulation of lipids. This Commentary covers the lipid droplet life cycle and highlights the early steps during lipid droplet biogenesis, which we propose to be the potential driving forces of lipid droplet diversification.

/pdf/the-why-when-and-how-of-lipid-droplet-diversity-1phx2bkqv8.pdf

The why, when and how of lipid droplet diversity.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17β-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17β-HSD family plays an important role in lipid metabolism, 17β-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17β-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17β-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17β-HSD13 as a pathogenic protein in the development of NAFLD.

https://www.pnas.org/content/pnas/111/31/11437.full.pdf

Hua-Min Xu

Papers

Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease.